KR20140020851A - Methods for treating metabolic disorders and obesity with gip and glp-1 receptor-active glucagon-based peptides - Google Patents

Abstract

Extended half-life GLP-1 / GIP adjuvant in patients in need thereof to reduce weight gain, cause weight loss, treat hyperglycemia, reduce blood sugar levels, or normalize blood sugar levels Methods of administering peptides are provided.

Description

METHODS FOR TREATING METABOLIC DISORDERS AND OBESITY WITH GIP AND GLP-1 RECEPTOR-ACTIVE GLUCAGON-BASED PEPTIDES} GIP and GLP-1 Receptor-Activated Glucagon-Based Peptides

Priority claim

This application claims priority to US Provisional Application No. 61 / 500,229 (filed June 23, 2011) and US Provisional Application No. 61 / 426,338 (filed December 22, 2010).

Merging by Reference of Electronically Submitted Materials

The computer readable nucleotide / amino acid sequence listing, filed concurrently herein and identified as follows, is incorporated by reference in its entirety: One 285,688 byte ASCII named "45708A_SeqListing.txt.", Created December 22, 2011. (Text) file.

Field of invention

The present invention generally relates to methods of administering extended half-life GLP-1 / GIP coagent peptides. In particular, the present invention provides methods for reducing weight gain or causing weight loss through the administration of an extended half-life GLP-1 / GIP coagent peptide, and for treating hyperglycemia, reducing blood sugar levels or normalizing blood glucose levels. It is about a method.

Type II diabetes (ie, type 2 diabetes) is a heterogeneous group of conditions that constitute approximately 90% of diabetes in the United States. Type 2 diabetes is caused by a combination of insulin resistance and reduced insulin secretion. Weight loss in obese patients is associated with improved insulin resistance and improved diabetes symptoms.

There are five broadly approved classes of oral antidiabetics, namely sulfonylureas, biguanides, meglitinides, thiazolidinediones and alpha-glycosidase inhibitors. Treatment of type 2 diabetes usually involves selecting one or more of these oral formulations as initial therapy (see, eg, Charpentier G. Diabetes Metab. Res. Rev. 18 (Supp. 3): S70-S76 (2002). )] Reference). However, despite the use of multiple drugs, full control of diabetes is still inadequate. Only 49.8% of people with diabetes achieve the National Diabetes Association target HbA _1c of less than 7%. Instead, 29.7% of people with diabetes have more than 8% HbA _1c (see, eg, Resnick et al., Diabetes Care 29: 531-537 (2006)).

Incretin hormones, glucagon-like peptide-1 (GLP-1), and glucose dependent insulinotropic peptides (GIP) are naturally occurring peptides. It is a hormone. Both GLP-1 and GIP stimulate insulin synthesis and secretion in a glucose dependent manner and do not develop hypoglycemia (see, eg, Nauck et al., J. Clin. Endocrinol. Metab. 76: 912-917 (1993). And Irwin et al., Regul.Pept. 153: 70-76 (2009)).

GLP-1 is effective as an adjuvant therapy for diabetes. GLP-1 therapy is associated with weight loss but is also associated with nausea that occurs in at least 20% of patients treated with GLP-1 analogs.

 One aspect of the invention provides about 1 mg to about 40 mg, or about 4 mg to about 30 mg of an extended half-life GLP-1 / GIP coagent peptide in adult humans in need of reducing weight gain or inducing weight loss. Or a total weekly dose of about 4 to about 20 mg, or about 10 to about 20 mg, or about 2 to about 10 mg, to provide a method for reducing weight gain or causing weight loss in an adult human being. (Eg, the adult human has overweight, type II diabetes, insulin resistance, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD) or metabolic syndrome).

Another aspect of the invention provides about 1 mg to about 40 mg, or about 4 mg of an extended half-life GLP-1 / GIP coagent peptide in adult humans in need of treatment of hyperglycemia, reduction of blood glucose levels or normalization of blood glucose levels. Treating hyperglycemia or treating blood glucose levels in the adult human, comprising administering a total weekly dose of from about 30 mg, or about 4 to about 20 mg, or about 10 to about 20 mg, or about 2 to about 10 mg. To reduce or normalize blood glucose levels.

Extended half-life GLP-1 / GIP coagent peptides typically have a GIP percent potency of at least 1% or a GLP-1 percent titer of at least 1%. In some embodiments, the extended half-life GLP-1 / GIP coagent peptide expresses GLP-1 percent titer within about 10 times the GIP percent titer. Alternatively, in some embodiments, the extended half-life GLP-1 / GIP coagent peptide expresses EC ₅₀ at the GLP-1 receptor within 10 times of EC ₅₀ at the GIP receptor. In any of these embodiments, for example, the extended half-life GLP-1 / GIP coagent peptide expresses a half-life of about 4 to about 10 days, or about 4 to about 7 days. In any of these embodiments, administration of the prolonged half-life GLP-1 / GIP coagent peptide may be due to an increase in insulin levels, a decrease in glucose levels, an increase in C-peptide levels, a decrease in HbA _1c levels, or fructosamine May result in a decrease in levels, or any combination thereof.

The extended half-life GLP-1 / GIP coagent peptide is administered alone or in combination with a second therapeutic agent (e.g., antidiabetic and / or anti-obesity agent) at any cycle that results in a total weekly dose listed. For example, once per week or twice per week).

In some embodiments, the extended half-life GLP-1 / GIP coagent peptide comprises one or more hydrophilic polymer moieties having a collective molecular weight of about 30,000 Daltons to about 60,000 Daltons (eg, about 40,000 Daltons). Include. Non-limiting examples of extended half-life GLP-1 / GIP coagent peptides include any of SEQ ID NOs: 5-94, 99-169, 173-413, such as sequences that maintain at least 10% of GIP or GLP-1 activity. An amino acid sequence having up to 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid modifications for SEQ ID NOs: 5 to 94, 99 to 169, 173 to 413, or SEQ ID NOs: 5 to 94, 99 to 169, 173 to 413 PEGylated derivatives. For example, the extended half-life GLP-1 / GIP coagent peptide may comprise any of SEQ ID NOs: 75, 99-103, 140, 153, 166, and 261.

Extended half-life GLP-1 / GIP coagent peptides can be administered to sterile pharmaceutical compositions by subcutaneous, intravenous or intramuscular injection, and the like.

1 is a Phase 1, randomized, placebo-controlled, positive-controlled two-part study conducted in healthy male (male) and female (cancer) subjects to assess the effect of dose range on beta cell response on glucose loading. Shows the result. Human subjects received placebo or 4 mg, 8 mg or 16 mg of extended half-life GLP-1 / GIP coagent peptide and insulin secretion rate was measured. A dose dependent, dose proportional increase in insulin secretion rate (ISR) was observed after treatment with the extended half-life GLP-1 / GIP coagent peptide compared to placebo.
FIG. 2 depicts the results of a Phase 1, randomized, placebo-controlled, positive-controlled two-part study conducted in healthy male and female subjects to assess the effect of the dose range on the beta cell response on glucose loading. Human subjects receive a placebo or 4 mg (FIG. 2A) or 8 mg (FIG. 2B) extended half-life GLP-1 / GIP coagent peptide and glucose infusion at a rate of 0-12 mg / kg / min and plasma glucose levels Was measured.
FIG. 3 shows the results of experiments comparing C-peptide levels in subjects receiving 4 mg, 8 mg or 16 mg of extended half-life GLP-1 / GIP coagent peptide and glucose infusion at 0-12 mg / kg / min. Shows.
FIG. 4 is a comparison of the appearance of plasma acetaminophen over 4 hours in subjects administered BYETTA or 4 mg, 8 mg or 16 mg of extended half-life GLP-1 / GIP coagent peptide. FIG. .

 The prolonged half-life GLP-1 / GIP coagent peptide, as described in PCT Patent Application Publication No. WO 2010/011439 (incorporated herein by reference in its entirety), not only treats hyperglycemia, including diabetes, but also supports weight gain. It has been found to be useful for reducing or causing weight loss. These peptides provide greater weight loss compared to GLP-1 alone. Extended half-life GLP-1 / GIP coagent peptides have extended circulatory half-lives (eg, about 5 to 5), such as allowing dosing at longer intervals (eg, once a week or even once every two weeks). 6 days).

Without intending to be bound by any particular theory, extended half-life GLP-1 / GIP coagent peptides are similar or superior to current GLP-1 therapies, with reduced incidence of gastrointestinal resistance, such as nausea or vomiting. Demonstrate hypoglycemic and weight loss effects.

The extended half-life GLP-1 GIP coagent peptide expressed glucose normalization and weight loss properties in various animal models. In lean mice and rats, these peptides provide improved resistance to glucose control. In diet-induced obese mice, these peptides reduced both food intake and weight gain.

In a phase 1, randomized, placebo-controlled, sequential, single-rising dose study of extended half-life GLP-1 / GIP coagent peptide (see Example 1), a single of extended half-life GLP-1 / GIP coagent peptide Doses were administered to healthy male volunteers by subcutaneous (SC) injection ranging from 0.1 mg up to 32 mg. Each of the doses was well tolerated and was not associated with adverse events, clinically significant laboratory findings or ECG findings.

In a Phase 1, randomized, placebo-controlled, positive-controlled, two-part study (see Example 2), subcutaneous (SC) injections of placebo and Bayetta SC injection of BYETTA® (Amylin Pharmaceuticals) was done as a positive control. Subjects in two sections of the study were given SC injections of placebo and SC injections of extended half-life GLP-1 / GIP coagent peptide. Extended half-life GLP-1 / GIP coagent peptides at 4 mg, 8 mg and 16 mg doses increased insulin secretion in a dose dependent manner during stepwise glucose infusion without effects on gastric emptying.

Justice

As used herein, the term "peptide" includes a sequence of three or more amino acids, typically less than 100 or less than 50 amino acids, wherein the amino acids are naturally or non-naturally occurring) amino acids. Non-natural amino acids refer to amino acids that do not occur naturally in vivo but can nevertheless be incorporated into the peptide structures described herein.

As used herein, the term "GLP-1 / GIP coagent peptide" refers to a peptide that expresses activity at both the GLP-1 receptor and the GIP receptor. Such peptides may be selectively undetectable or have relatively low glucagon activity (eg, at least 10-fold lower percent titer or at least 100-fold lower titer at the glucagon receptor compared to the GLP-1 receptor or GIP receptor).

 As used herein, the term “extended half-life” refers to a peptide with extended duration of action and / or reduced clearance rate. For example, extended periods of action may result in conjugation and / or dies to heterologous moieties (eg, polyethylene glycol (PEG), albumin, or Fc regions or fragments thereof) that extend circulating half-life. Resistance to peptidase IV cleavage.

As used herein, the general term “polyethylene glycol” or “PEG” is a branched chain, represented by the general formula H (OCH ₂ CH ₂ ) _n OH where n is at least 9 Or a mixture of condensation polymers of ethylene oxide and water, in straight chain form.

As used herein, the term "pegylated" and the like refers to compounds modified from their natural state by linking one or more polyethylene glycol moieties to the compound. A “pegylated extended half-life GLP-1 / GIP coagent peptide” is covalently linked to an extended half-life GLP-1 / GIP coagent peptide, eg, at a collective molecular weight of PEG from about 30,000 daltons to about 60,000 daltons. Extended half-life GLP-1 / GIP coagent peptide with one or more PEG chains.

As used herein, amino acid "modification" refers to the substitution, addition or deletion of an amino acid, and substitution with any of the 20 amino acids commonly found in human patients as well as atypical or non-natural amino acids. Its addition. Throughout this application, all references to specific amino acid positions (eg, position 28) by number refer to amino acids at that position in natural glucagon (SEQ ID NO: 1) or at the corresponding amino acid position in any analog thereof. do. For example, reference to “position 28” in this specification shall mean the corresponding position 27 relative to the peptide from which the first amino acid of SEQ ID NO: 1 is deleted. Likewise, reference to “position 28” herein shall refer to position 29 corresponding to a peptide to which one amino acid is added before the N-terminus of SEQ ID NO: 1. Commercial sources of atypical amino acids include Sigma-Aldrich (Milwaukee, WI), KempPep Inc. (Miami, FL) and Genzyme Pharmaceuticals ( Genzyme Pharmaceuticals), Cambridge, Massachusetts. Atypical amino acids can be purchased from commercial suppliers, newly chemically synthesized, chemically modified or derivatized from other amino acids.

As used herein, amino acid "substitution" refers to the replacement of one amino acid residue with a different amino acid residue.

As used herein, the term "conservative amino acid substitution" is used herein to refer to one amino acid as another amino acid having similar properties such as size, charge, hydrophobicity, hydrophilicity and / or aromaticity. Defined as a substitute for, includes exchange within one of five groups:

I. Small aliphatic, nonpolar or somewhat polar residues:

Ala, Ser, Thr, Pro, Gly;

II. Polar, negatively charged residues and their amides and esters:

Asp, Asn, Glu, Gln, cysteic acid and homocysteic acid;

III. Polar, positively charged residues:

His, Arg, Lys; Ornithine (Orn)

IV. Large, aliphatic, nonpolar residues:

Met, Leu, Ile, Val, Cys, Norleucine (Nle), Homocysteine

V. Large, Aromatic Residues:

Phe, Tyr, Trp, Acetyl Phenylalanine

As used herein, the term "natural glucagon" refers to a peptide consisting of the amino acid sequence of SEQ ID NO: 1, the term "natural GIP" refers to a peptide consisting of the amino acid sequence of SEQ ID NO: 4, and "natural The term GLP-1 "means GLP-1 (7-36) amide (consisting of the amino acid sequence of SEQ ID NO: 3), GLP-1 (7-37) acid (consisting of the amino acid sequence of SEQ ID NO: 2), or both compounds General term for a mixture of As used herein, the generic reference to "glucagon" or "GIP" or "GLP-1" without any further designation is intended to mean natural glucagon or natural GIP or natural GLP-1, respectively.

As used herein, general reference to peptides is intended to include peptides with modified amino and carboxy termini. For example, amino acid chains containing amide groups instead of terminal carboxylic acids are intended to be encompassed by amino acid sequences that refer to standard amino acids.

As used herein, the term “selectivity” of a molecule relative to a first receptor relative to a second receptor refers to the following ratio: EC ₅₀ of the molecule at the second receptor is determined by the molecular weight of the molecule at the first receptor. Divided by EC ₅₀ . For example, a molecule with 1 nM of EC _{50 in} the first receptor and 100 nM of EC ₅₀ in the second receptor has a 100-fold selectivity for the first receptor for the second receptor.

, Is a value obtained by dividing the EC ₅₀ of GLP-1 on GLP-1 GLP-1 peosenteu titer of the EC ₅₀ to the extended half-life of GLP-1 / GIP co-agent peptide multiplying 100% As used in this specification.

As used herein, the GIP percent titer is 100% of the EC ₅₀ of GIP divided by the EC ₅₀ of the extended half-life GLP-1 / GIP coagent peptide.

, Is a value obtained by dividing the EC ₅₀ of the glucagon glucagon percent titer of the EC ₅₀ to the extended half-life of GLP-1 / GIP co-agent peptide multiplying 100% As used in this specification.

 As used herein, the term “treating” includes preventing a particular disorder or condition, or alleviating and / or preventing or eliminating a symptom associated with a particular disorder or condition. For example, as used herein, the term “treating diabetes” will generally refer to altering blood glucose levels in the direction of normal levels, and includes increasing or decreasing blood glucose levels according to a given situation. Can be.

The term “parenteral” means not through the digestive tract but by some other route, such as subcutaneous, intramuscular, spinal or intravenous.

 As used herein, the term "pharmaceutically acceptable carrier" refers to standard pharmaceutical carriers such as phosphate buffered saline solutions, water, emulsions such as oil / water or water / oil emulsions, and various types of One of the humectants. The term also includes any of the agents approved by the US Federal Regulatory Authority listed in the US Pharmacopoeia for use in animals, including humans.

As used herein, the term “pharmaceutically acceptable salts” refers to salts of compounds that retain the biological activity of the parent compound which is not biologically or otherwise undesirable. Many of the compounds disclosed herein can form acid and / or base salts due to the presence of amino and / or carboxyl groups or groups similar thereto.

 Pharmaceutically acceptable base addition salts can be prepared from inorganic bases and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines.

 Pharmaceutically acceptable acid addition salts can be prepared from inorganic acids and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, maldelic acid, methanesulfonic acid, ethanesulfuric acid Phonic acid, p-toluene-sulfonic acid, salicylic acid and the like.

GLP-1 / GIP Coagent Peptide Embodiments

The invention described herein relates to a method of administering an extended half-life GLP-1 / GIP coagent peptide to an adult human in need thereof. GLP-1 / GIP coagent peptides and extended half-life versions of such peptides are described exclusively in WO 2010/011439, which is incorporated herein by reference in its entirety.

In some embodiments, the extended half-life GLP-1 / GIP coagent peptide comprises (a) SEQ ID NOs: 5 to 94, corresponding to SEQ ID NOs: 5 to 94, 99 to 169, and 173 to 262 in WO 2010/011439; 99-169 and 173-262, (b) in SEQ ID NOs 263-277 corresponding to SEQ ID NOs: 19-28 and 33-36 in US Provisional Application No. 61 / 29,8812, which is incorporated herein by reference. Any one or (c) any one of SEQ ID NOs: 178-413, and (d) up to 2, 3, 4, 5, 6, 7, 8, 9 or 10 further modifications (eg, conservative substitutions) Any analog of any of the above peptides having one or more amino acid modifications, or (e) the analogs have the desired activity (eg, at least 1%, 10%, 20%) of the parent peptide at the GLP-1 and GIP receptors PEGylated derivatives of any one of the above peptides under the condition of (30%, 40% or 50%) Any one or the same. WO 2010/011439 also provides some guidance regarding amino acids that can be changed; The invention also adds at one or more of positions 1, 2, 5, 7, 8, 10, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 24, 27, 28 or 29. A peptide having a, deletion, non-conservative substitution and / or non-conservation substitution is assumed. Peptides and analogs may comprise additional heterologous moieties comprising one or more PEG chains or one or more additional amino acid sequences (such as fusion proteins) resulting in the PEGylated derivative of any one of SEQ ID NOs: 1-413. In some exemplary embodiments, the extended half-life GLP-1 / GIP coagent peptide is any one of SEQ ID NOs: 75, 99-103, 140, 153, 166, and 261. It is understood that analogs are produced by new synthesis rather than sequentially producing parent peptides that are modified, in some cases, for example, pegylated, but it is understood that the parent peptides can then be prepared first and then pegylated.

In some embodiments, the EC ₅₀ of the half-life GLP-1 / GIP coagent peptide extended at the GIP receptor is about 20 times, higher or lower than its EC ₅₀ at the GLP-1 receptor Or preferably about 10 times, 9 times, 8 times, 7 times, 6 times, 5 times, 4 times, 3 times or about 2 times. In some embodiments, the extended half-life GLP-1 / GIP coagent peptide is about 20 times, about 15 times, or preferably about 10 times, 9 times, 8 times, 7 times, 6 different from the GIP percent titer. It expresses GLP-1 percent titer within fold, 5 fold, 4 fold, 3 fold or about 2 fold. In an exemplary embodiment (eg, in any of the embodiments herein), the extended half-life GLP-1 / GIP coagent peptide has a GIP percent of at least about 1%, at least about 5% or at least about 10%. Express titer. In an exemplary embodiment (eg, in any of the embodiments herein), the extended half-life GLP-1 / GIP coagent peptide expresses a GLP-1 percent titer of at least about 1%. In some embodiments, the extended half-life GLP-1 / GIP coagent peptide is less than about 10%, such as about 1-10%, or about 0.1-10%, or more than 0.1% of the activity of natural glucagon at the glucagon receptor. Less than 10%. In any of the embodiments herein, for example, the selectivity of the extended half-life GLP-1 / GIP coagent peptide relative to the GLP-1 receptor is less than 100-fold, or GIP percent, as compared to the GIP receptor. The ratio of GLP-1 percent titers divided by titer is less than 100, less than about 20, 15, 10, 9, 8, 7, 6 or 5.

Extended half-life GLP-1 / GIP coagent peptides have extended duration of action, such as due to extended circulating half-life (eg, about 5 to 6 days), which means that dosing at longer intervals (eg, weekly dosing, Biweekly administration). In some embodiments, the extended half-life GLP-1 / GIP coagent peptide used in accordance with the present invention is about 3 to about 15 days, such as about 3 to 5, 3 to 6, 3 to 7, 3 to 8, 3 To 9, 3 to 10, 3 to 11, 3 to 12, 3 to 13, 3 to 14, 3 to 15, 4 to 5, 4 to 6, 4 to 7, 4 to 8, 4 to 9, 4 to 10 , 4 to 11, 4 to 12, 4 to 13, 4 to 14, 4 to 15, 5 to 6, 5 to 7, 5 to 8, 5 to 9, 5 to 10, 5 to 11, 5 to 12, 5 Half-life ranging from 12 to 5, 14, 5 to 15, 6 to 7, 6 to 8, 6 to 9, 6 to 10, 6 to 11, 6 to 12, 6 to 13, 6 to 14 or 6 to 15 days Has In some embodiments, the extended half-life GLP-1 / GIP coagent peptide receives a full clearance of about 10 days to about 30 days, eg, about 20 days.

 For example, the extended duration of action may be due to reduced or susceptibility to dipeptidase IV cleavage and / or conjugation to heterologous moieties that prolong circulating half-life. Resistance or reduced susceptibility to dipeptidase IV cleavage is provided by, for example, amino acid modifications (for “DPP-IV protecting amino acids”) at positions 1 and / or 2. Examples of suitable substitutions include D-histidine, alpha, alpha-dimethyl imidazole acetic acid (DMIA), N-methyl histidine, alpha-methyl histidine, imidazole acetic acid, desaminohistidine, hydroxyl-histidine, acetyl at position 1 Histidine or homo-histidine; Or D-serine, D-alanine, valine, glycine, N-methyl serine or alpha-aminoisobutyric acid (AIB) at position 2.

Examples of heterologous moieties that extend the duration of action include acyl or alkyl groups; Dipeptide precursor moieties (eg, linked via amide or ester bonds) or other precursor moieties; Polyethylene glycol (PEG) or other hydrophilic polymers; Albumin or other plasma proteins; Fc regions of immunoglobulins or fragments thereof; rPEG, but are not limited to these. Such ingredients are known in the art. For example, acylation or alkylation, hydrophilic polymers, albumin or other plasma proteins, and Fc regions of immunoglobulins or fragments thereof are described in WO 2010/011439, which is incorporated by reference in its entirety. Are merged. Ester precursor moieties are described in WO2009 / 099763, which is incorporated by reference in its entirety, and amide precursor moieties are described in WO 2010/071807. The literature is incorporated by reference in its entirety). Recombinant PEG or rPEG is described in WO2009 / 023270.

In some embodiments, the extended half-life GLP-1 / GIP coagent peptide is a C-terminal extension (eg, 30, 31, 32, 33, 34, 35, 36, as described in WO 2010/011439). At any of amino acid positions 16, 17, 20, 21, 24 or 29 after position 29 at the amino acid added within 37, 38, 39 (eg position 30), or at the C-terminal amino acid (eg 40, 41, 42, or more) and amino acids covalently linked to the hydrophilic polymer. In an exemplary embodiment, this hydrophilic polymer is covalently linked to Lys, Cys, Orn, homocysteine or acetyl-phenylalanine residues at either of these positions. Exemplary hydrophilic polymers include one or more polyethylene glycol (PEG) chains having a collective molecular weight of about 20,000 Daltons to about 40,000 Daltons, as described, for example, in WO 2010/011439. In some embodiments, the polyethylene glycol polymer has a molecular weight of about 30,000 Daltons to about 60,000 Daltons, or about 30,000 Daltons to about 50,000 Daltons (eg, 40, 000 Daltons).

Heterogeneous moieties

As used herein, the term “heterologous moiety” is synonymous with “conjugated moiety” and refers to any molecule other than the attached peptide (chemical or biochemically native or unencrypted). . In some embodiments, the heterologous moiety is another peptide or protein. In some embodiments, the heterologous moiety is a plasma protein, such as albumin, transferrin, fibrinogen and globulin. In some embodiments, the plasma protein is albumin or transferrin.

In some embodiments, the heterologous moiety is a Fc portion of an immunoglobulin (Ig), or a fragment or modified analog thereof, such as a fragment that retains an IgG, IgA, IgE, IgD or IgM, preferably FcRn binding site. . The Fc region is the C-terminal region of the Ig heavy chain, which binds to an Fc receptor (FcRn) that performs activities such as recycling the immunoglobulins and circulating them back, resulting in an extended half-life. For example, according to some definitions, the human IgG heavy chain Fc region is stretched from Cys226 to the C-terminus of the heavy chain. The region of the Fc portion of the IgG that binds to the FcRn receptor is described by X-ray crystallography (Burmeister et al. 1994, Nature 372: 379). The main contact region of Fc with FcRn is near the junction of the CH2 domain and the CH3 domain, and the amino acid residues 248, 250 to 257, 272, 285, 288, 290 to 291, 308-311 and 314 of the CH2 domain, and the CH3 domain Amino acid residues of 385 to 387, 428 and 433 to 436; Some conjugate moieties may or may not include binding site (s) to FcγRs responsible for ADCC and CDC, or may include modifications designed to reduce ADCC or CDC.

In some embodiments, the heterologous moiety is a polymer. In some embodiments, the polymers are polyamides, polycarbonates, polyalkylenes and derivatives thereof (including polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates), acrylic acid and methacrylic acid esters Polymer (poly (methyl methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate), poly (isobutyl methacrylate), poly (hexyl methacrylate), poly (isodecyl methacrylate) Rate), poly (lauryl methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate) and poly (octadecyl acrylate) Polyvinyl polymer (including polyvinyl alcohol, polyvinyl ether, polyvinyl ester, polyvinyl halide, poly (vinyl acetate) and polyvinylpyrrolidone), Polyglycolide, polysiloxane, polyurethane and copolymers thereof, cellulose (alkyl cellulose, hydroxyalkyl cellulose, cellulose ether, cellulose ester, nitro cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxy-propyl methyl Cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxyethyl cellulose, cellulose triacetate and cellulose sulfate sodium salt), polypropylene, polyethylene (poly (ethylene Glycol), poly (ethylene oxide) and poly (ethylene terephthalate)), and polystyrene.

 In some aspects, the polymer may be a biodegradable polymer, such as a synthetic biodegradable polymer (eg, a polymer of lactic and glycolic acids, polyanhydrides, poly (ortho) esters, polyurethanes, poly (butyric acids), poly ( Valeric acid), and poly (lactide-cocaprolactone)), natural biodegradable polymers (such as alginates and other polysaccharides including dextran and cellulose, collagen, chemical derivatives thereof (chemical groups such as alkyl, Addition, substitution, hydroxylation, oxidation of alkylene, and other modifications commonly performed by one of ordinary skill in the art), albumin and other hydrophilic proteins (eg zein and other prolamin and hydrophobic proteins), as well as Arbitrary copolymers or mixtures thereof.

 In some aspects, the polymer is a bioadhesive polymer, such as H. S. Sawhney, CP Pathak and JA Hubbell in Macromolecules, 1993, 26, 581-587 (the teachings of this document are incorporated herein), bioerodible hydrogels, polyhyaluronic acid, casein, gelatin , Glutin, polyanhydride, polyacrylic acid, alginate, chitosan, poly (methyl methacrylate), poly (ethyl methacrylate), poly (butyl methacrylate), poly (isobutyl methacrylate), poly (Hexyl methacrylate), poly (isodecyl methacrylate), poly (lauryl methacrylate), poly (phenyl methacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly ( Isobutyl acrylate) and poly (octadecyl acrylate).

In some embodiments, the polymer is a water soluble polymer or a hydrophilic polymer. Suitable water soluble polymers are known in the art and include, for example, polyvinylpyrrolidone, hydroxypropyl cellulose (HPC; Klucel), hydroxypropyl methylcellulose (HPMC; Methocel), Nitrocellulose, hydroxypropyl ethylcellulose, hydroxypropyl butyl cellulose, hydroxypropyl pentyl cellulose, methyl cellulose, ethyl cellulose (Ethocel), hydroxyethyl cellulose, various alkyl celluloses and hydroxyalkyl celluloses, various Cellulose ethers, cellulose acetates, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, vinyl acetate / crotonic acid copolymers, poly-hydroxyalkyl methacrylates, hydroxymethyl methacrylates, methacrylic acid copolymers, Polymethacrylic Acid, Polymethylmethacrylate, Maleic Anhydride / Methyl Vinyl Terpolymer, polyvinyl alcohol, sodium and calcium polyacrylic acid, polyacrylic acid, acidic carboxy polymer, carboxypolymethylene, carboxyvinyl polymer, polyoxyethylene polyoxypropylene copolymer, polymethylvinyl ether maleic anhydride, carboxymethyl Amides, potassium methacrylate divinylbenzene copolymers, polyoxyethylene glycols, polyethylene oxides, and derivatives, salts, and combinations thereof.

 In some embodiments, the heterologous moiety is a carbohydrate. In some embodiments, the carbohydrates are monosaccharides (e.g. glucose, galactose, fructose), disaccharides (e.g. sucrose, lactose, maltose), oligosaccharides (e.g. raffinose, starchiose), polysaccharides (starch, amylase, amylopectin , Cellulose, chitin, carlos, laminarin, xylan, met, fucoidan, galactomannan).

In some embodiments, the heterologous moiety is a lipid. Lipids may, in some embodiments, be fatty acids, eicosanoids, prostaglandins, leukotrienes, thromboxanes, N-acyl ethanolamines, glycereroids (eg, mono-, di-, tri-substituted glyces). Cerols), glycerophospholipids (e.g. phosphatidylcholine, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine), sphingolipids (e.g. sphingosine, ceramide), sterol lipids (e.g. steroids, cholesterol), prenol lipids, saccha Saccharolipids or polyketides, oils, waxes, cholesterol, sterols, fat-soluble vitamins, monoglycerides, diglylides, triglycerides, phospholipids

Hydrophilic polymer

Suitable hydrophilic polymers that give increased hydrodynamic radius and increased serum half-life include polyethylene glycol (PEG), polypropylene glycol, polyoxyethylated polyols (eg POG), polyoxyethylation Sorbitol, polyoxyethylated glucose, polyoxyethylated glycerol (POG), polyoxyalkylene, polyethylene glycol propionaldehyde, copolymer of ethylene glycol / propylene glycol, monomethoxy-polyethylene glycol Lycol, mono- (C1-C10) alkoxy- or aryloxy-polyethylene glycol, carboxymethylcellulose, polyacetal, polyvinyl alcohol (PVA), polyvinyl pyrrolidone, poly-1,3-dioxolane, Poly-1,3,6-trioxane, ethylene / maleic anhydride copolymer, poly (β-amino acid) (either homopolymer or random copolymer), poly (n-vinyl pyrrolidone) polyethylene glycol , Propylene writing Yikol include homopolymers (PPG) and other polyalkylene oxides, polypropylene oxide / ethylene oxide copolymers, colon acid (colonic acid) or other polysaccharide polymers, Ficoll (Ficoll) or dextran and mixtures thereof. Dextran is a polysaccharide polymer of glucose subunits bound mostly by α1-6 bonds. Dextran is available in various molecular weight ranges, such as about 1 kD to about 100 kD, or about 5, 10, 15 or 20 kD to about 20, 30, 40, 50, 60, 70, 80 or 90 kD.

One or more hydrophilic moieties, such as polyethylene glycol chains, attached to the peptide have a collective molecular weight selected from the range of about 20,000 Daltons to about 60,000 Daltons, according to some embodiments. In some embodiments, the polyethylene glycol chains have a molecular weight selected from about 500 to about 5,000 daltons, or about 1,000 to about 5,000 daltons. In another embodiment, hydrophilic moieties such as polyethylene glycol chains have a molecular weight of about 20,000 to about 60,000 Daltons. In another exemplary embodiment, the hydrophilic moiety, such as polyethylene glycol chain, has a collective molecular weight of about 30,000 to about 50,000 Daltons (eg, 40,000 Daltons). For example, two 20,000 Dalton PEG chains can be attached at the same or different positions of the peptide to achieve a collective molecular weight of 40,000 Daltons.

Linear or branched hydrophilic polymers are contemplated. The resulting formulation of the conjugate may be monodisperse or polydisperse in nature and may also have about 0.5, 0.7, 1, 1.2, 1.5 or more than two polymer moieties per peptide.

In some embodiments, the natural amino acid of the peptide is substituted with an amino acid having a side chain suitable for crosslinking with the hydrophilic moiety to facilitate binding of the hydrophilic moiety to the peptide. Exemplary amino acids include Cys, Lys, Orn, Homo-Cys or acetyl phenylalanine (Ac-Phe). In another embodiment, amino acids modified to include the hydrophilic group are added to the peptide at the C-terminus.

Auxiliary peptides that can form extended conformations similar to chemical PEG (eg, recombinant PEG (rPEG) molecules) are described in WO2009 / 023270 and US2008 / 0286808. rPEG molecules are not polyethylene glycol. The rPEG molecule is, in some aspects, a polypeptide comprising one or more of glycine, serine, glutamic acid, aspartic acid, alanine or proline. In some aspects, the rPEG is a homopolymer, such as poly-glycine, poly-serine, poly-glutamic acid, poly-aspartic acid, poly-alanine or poly-proline. In other embodiments, the rPEG is two types of repeated amino acids, such as poly (Gly-Ser), poly (Gly-Glu), poly (Gly-Ala), poly (Gly-Asp), poly (Gly-Pro). ), Poly (Ser-Glu) and the like. In some aspects, rPEG comprises three different types of amino acids, poly (Gly-Ser-Glu). In a specific aspect, rPEG increases the half-life of the extended half-life GLP-1 / GIP coagent peptide. In some aspects, the rPEG comprises a net positive charge or a net negative charge. rPEG lacks secondary structure in some aspects. In some embodiments, rPEG is at least 10 amino acids in length, and in some embodiments is about 40 to about 50 amino acids in length. The auxiliary peptide is, in some aspects, fused to the N- or C-terminus of the peptide of the invention via a peptide bond or protease cleavage site. rPEG includes in some aspects an affinity tag, or is linked to a PEG greater than 5 kDa.

Acylation or alkylation

In some embodiments, the extended half-life GLP-1 / GIP coagent peptide is a non-native acyl or alkyl group (eg, the incorporation of pre-acrylicated / alkylated amino acids, respectively, into the peptide, or the synthesis of the peptide after synthesis). Amino acids, including "acylated amino acids" or "alkylated amino acids" herein, regardless of how prepared, such as by silication / alkylation, and the like. Acyl or alkyl groups may be directly covalently linked to the amino acids of the peptide or indirectly covalently bonded to the amino acids of the peptide via spacers. Peptides may be acrylated at the same amino acid position to which the hydrophilic polymer is bound, or at different amino acid positions.

Acyl or alkyl groups can be of any size, can include carbon chains of any length, and can be straight or branched. In some exemplary embodiments of the invention, the acyl group is a C4 to C30 fatty acid. For example, the acyl group is any one of C4 fatty acid, C6 fatty acid, C8 fatty acid, C10 fatty acid, C12 fatty acid, C14 fatty acid, C16 fatty acid, C18 fatty acid, C20 fatty acid, C22 fatty acid, C24 fatty acid, C26 fatty acid, C28 fatty acid or C30 fatty acid Can be. In some embodiments, the acyl group is a C8 to C20 fatty acid, such as a C14 fatty acid or C16 fatty acid.

In another exemplary embodiment, the alkyl group is C4 to C30 alkyl. For example, the alkyl group is any one of C4 alkyl, C6 alkyl, C8 alkyl, C10 alkyl, C12 alkyl, C14 alkyl, C16 alkyl, C18 alkyl, C20 alkyl, C22 alkyl, C24 alkyl, C26 alkyl, C28 alkyl or C30 alkyl Can be. In some embodiments, the alkyl group is C8 to C20 alkyl, such as C14 alkyl or C16 alkyl.

In some embodiments, the acyl group is a bile acid, including but not limited to, cholic acid, kenodeoxycholic acid, deoxycholic acid, lithocholic acid, taurocholic acid, glycocholic acid and cholesterol acid.

Therapeutic Uses of Extended Half-Life GLP-1 / GIP Coagent Peptides

Extended half-life GLP-1 / GIP coagent peptides are described in WO 2010/011439, which is incorporated herein by reference in its entirety, to treat obesity and / or to lose weight (eg, lose weight). And / or normalize body fat distribution, prevent or reduce weight gain, and / or reduce appetite.

In one aspect, the present invention is directed to an adult human in need of reducing weight gain or inducing weight loss by administering an extended half-life GLP-1 / GLP coagent peptide at a weekly dose of about 1 mg to about 40 mg. A method for reducing weight gain or causing weight loss in humans. Methods to reduce weight gain or cause weight loss include treating overweight and obesity due to various causes, including drug-derived obesity, and treating vascular diseases (coronary artery disease, myocardial infarction, stroke, peripheral vascular disease, ischemic reperfusion). And the like), hypertension, the onset of type II diabetes, hyperlipidemia, and musculoskeletal disorders. Some methods are also expected to be particularly useful for obesity in patients with other risk factors for cardiovascular disease, such as insulin resistance or patients with type II diabetes, hypertension, hyperlipidemia, or a combination of these risk factors.

In some embodiments of this aspect of the invention, the adult human has any stage of nonalcoholic fatty liver disease (NAFLD), or any stage of alcoholic liver disease or alcohol-induced liver disease. NAFLD refers to a wide range of liver diseases ranging from simple fatty liver (fatosis) to nonalcoholic steatohepatitis (NASH) to cirrhosis. Both stages of NAFLD have a common accumulation of fat (fat infiltration) in liver cells (liver cells or hepatocytes). Simple fatty liver is an abnormal accumulation of certain types of fat (eg, triglycerides) in liver cells without inflammation or scarring. In NASH, fat accumulation is associated with varying degrees of inflammation (hepatitis) and scarring (fibrosis) in the liver. Inflammatory cells can destroy liver cells (hepatocyte necrosis). In the terms "steatohepatitis" and "steatonecrosis", steato refers to fat infiltration, hepatitis refers to inflammation of the liver, and necrosis refers to destroyed liver cells. NASH can ultimately lead to hepatic scarring (fibrosis) followed by irreversible advanced scarring (cirrhosis). Liver cirrhosis caused by NASH is the final most severe stage in the NAFLD range (Mendler, Michel, "Fatty Liver: Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH)", ed. Schoenfield, Leslie J., MedicineNet.com, August 29, 2005).

Alcoholic liver disease includes three pathologically distinct liver diseases associated with or caused by excessive consumption of alcohol: fatty liver (fatosis), chronic or acute hepatitis, and cirrhosis. Alcoholic hepatitis ranges from mild hepatitis, where abnormal laboratory tests are only symptoms of disease, from jaundice (yellow skin due to bilirubin stagnation), hepatic encephalopathy (nerve dysfunction caused by liver failure), ascite (to the abdomen). Severe liver dysfunction with complications such as fluid accumulation), hemorrhagic esophageal varices (various varicose veins in the esophagus), abnormal blood coagulation and lethargy. Histologically, alcoholic hepatitis has a characteristic appearance with swelling degeneration of hepatocytes, infection of neutrophils and sometimes malolithic bodies (abnormal aggregation of cellular intermediate fiber proteins). Cirrhosis is anatomically characterized by a broad nodule of the liver combined with fibrosis (Worman, Howard J., "Alcoholic Liver Disease", Columbia University Medical Center website).

The method of treatment in this embodiment of the present invention includes one, two, three or more reductions in the following: liver fat content, onset or progression of cirrhosis, development of hepatocellular carcinoma, abnormal liver enzyme levels (eg, Signs of inflammation such as aspartate aminotransferase AST and / or alanine aminotransferase ALT, or LDH), elevated serum ferritin, elevated serum bilirubin, and / or signs of fibrosis such as elevated TGF-beta levels. In a preferred embodiment, the extended half-life GLP-1 / GIP coagent peptide is used to treat patients who progress beyond simple fatty liver (fatosis) and show signs of inflammation or hepatitis. Such a method may, for example, result in a reduction in AST and / or ALT levels.

In some embodiments of this aspect of the invention, the adult human has metabolic syndrome. Metabolic syndrome, also known as metabolic syndrome X, insulin resistance syndrome or Reaven's syndrome, is a disorder that affects more than 50 million Americans. Subject syndromes are typically characterized by clustering of at least three or more of the following risk factors: (1) abdominal obesity (excessive adipose tissue in and around the abdomen), (2) atherosclerotic dyslipidemia (Blood fat disorders, including high triglycerides, low HDL cholesterol, and high LDL cholesterol that increase plaque buildup in the lining of the arteries), (3) elevated blood pressure, (4) insulin resistance or glucose intolerance, (5) Side-thrombotic state (eg, high fibrinogen or plasminogen activator inhibitor-1 in blood) and (6) inflammatory state (eg, elevated C-reactive protein in blood). Other risk factors may include aging, hormonal imbalance and genetic predisposition.

Metabolic syndrome is associated with an increased risk of coronary heart disease and other disorders associated with the accumulation of vascular plaques, such as stroke and peripheral vascular disease, referred to as atherosclerotic cardiovascular disease (ASCVD). Metabolic syndrome patients can progress from their insulin resistance state in their early stages to fully advanced type II diabetes, which further increases the risk of ASCVD. Without wishing to be bound by any particular theory, the relationship between insulin resistance and metabolic syndrome and vascular disease can be attributed to impaired insulin-stimulated vasodilation, reduced insulin resistance-associated NO availability due to increased oxidative stress, and adipo. It may be involved in one or more concurrent pathogenesis mechanisms including abnormalities of adipocyte-derived hormones such as pectin (Lteif and Mather, Can. J. Cardiol. 20 (suppl. B): 66B-76B (2004)).

According to the 2001 International Cholesterol Education Program Adult Treatment Panel (ATP III), any three of the following characteristics in the same individual meet the criteria for metabolic syndrome: (a) Abdominal obesity (102 cm or more in men, women) Waist at least 88 cm); (b) serum triglycerides (150 mg / dl or more); (c) HDL cholesterol (40 mg / dl or less in men, 50 mg / dl or less in women); (d) blood pressure (130/85 or higher); And (e) fasting blood sugar (110 mg / dl or more). According to the World Health Organization, individuals with high insulin levels (elevated fasting glucose or elevated postprandial sugar alone) with at least two of the following criteria meet the criteria for metabolic syndrome; (a) abdominal obesity (waist to hip ratio greater than 0.9, body mass index of at least 30 kg / m 2 or waist dimension greater than 37 inches); (b) a panel of cholesterol showing triglyceride levels of at least 150 mg / dl or HDL cholesterol below 35 mg / dl; (c) 140/90 or higher blood pressure (or during treatment for hypertension) (Mathur, Ruchi, "Metabolic Syndrome", ed. Shiel, Jr., William C., MedicineNet.com, May 11, 2009).

For purposes herein, the individual is considered to have metabolic syndrome if the individual meets the criteria of any or both of the criteria set forth in the 2001 International Cholesterol Education Program Adult Treatment Panel or the WHO.

In another aspect, the present invention provides a method of treating hyperglycemia in an adult human by administering the extended half-life GLP-1 / GLP coagent peptide to an adult human in need thereof at a weekly dose of about 1 mg to about 40 mg. And reducing blood sugar levels or normalizing blood sugar levels (eg, returning blood sugar levels to normal, eg, lowering blood sugar levels above normal). This method of treating hyperglycemia is also useful for various types of hyperglycemia, including insulin-dependent or insulin-independent diabetes (eg, type I diabetes, type II diabetes, or gestational diabetes), as well as kidney disease, retinal disease, and vascular disease. It is expected to be useful for reducing diabetes complications. As such, in some embodiments, the adult human has type I diabetes, type II diabetes, or gestational diabetes.

In some embodiments, administration of the prolonged half-life GLP-1 / GIP coagent peptide may include increasing insulin levels, decreasing glucose levels, increasing C-peptide levels, decreasing HbA _1c levels, decreasing fructosamine levels, And combinations thereof. Increasing insulin levels will indicate that administration of an extended half-life GLP-1 / GIP coagent peptide is effectively treating diabetes; The decrease in glucose levels will indicate that administration of the prolonged half-life GLP-1 / GIP coagent peptide acts to reduce blood glucose levels, thereby treating hyperglycemia.

HbA _1c levels depend on blood glucose concentrations (ie, higher blood glucose concentrations, higher HbA _1c levels), but are not affected by daily fluctuations in blood glucose concentrations. Instead, the levels represent average blood glucose levels of the last four weeks, which are strongly weighted for the most recent two weeks. Reduction of HbA _1c levels would indicate that administration of the extended half-life GLP-1 / GIP coagent peptide is reducing the average blood glucose level over the long term.

 The C-peptide acts as a linker between the A and B chains of insulin to facilitate efficient aggregation, folding and processing of insulin in the cytoplasmic reticulum. High levels of C-peptides generally show high levels of endogenous insulin production, while low levels of C-peptides generally show low levels of insulin production. Increasing C-peptide levels indicates that administration of an extended half-life GLP-1 / GIP coagent peptide is increasing insulin production.

Fructosamin can be used to check plasma glucose concentrations. In general, the higher the fructosamine concentration, the higher the average plasma level. Normal fructosamine levels may indicate that the patient is not diabetic or that the patient is a good diabetic control. An increase in fructosamine levels indicates an increase in the mean glucose of the patient over the last two to three weeks. Reduction of fructosamine levels will indicate that administration of an extended half-life GLP-1 / GIP coagent peptide is reducing average blood glucose levels.

In some embodiments, the extended half-life GLP-1 / GIP coagent peptide may be administered alone or in combination with an effective amount of one or more second therapeutic agents. In some embodiments, the second therapeutic agent is an antidiabetic, anti-obesity, or mixture thereof. Antidiabetic agents known or under study in the art include insulin, sulfonylureas such as tolbutamide (Orinase), acetohexamide (Dymelor), tolazaamide (tolinase ( Tolinase)), chlorpropamide (Diabinese), glyphide (Glucotrol), glyburide (Diabeta, Micronase, Glynase )), Glymepride (Amaryl), or glyclazide (Diamicron); Meglitinides such as repaglinide (Prandin) or nateglinide (Starlix); Biguanides such as metformin (Glucophage) or phenformin; Thiazolidinediones such as rosiglitazone (Avandia), pioglitazone (Actos), or troglitazone (Rezulin), or other PPARγ inhibitors; Alpha glycosidase inhibitors that inhibit carbohydrate digestion such as myglytol (Glyset), acarbose (Precose / Glucobay); Exenatide (bieta) or frraminide; Dipeptidyl peptidase-4 (DPP-4) inhibitors such as bildagliptin or cytagliptin; SGLT (sodium-dependent glucose transporter 1) inhibitors; Glucokinase activators (GKA); Glucagon receptor antagonist (GRA); Or FBPase (fructose 1,6-biphosphatase) inhibitors. For example, an extended half-life GLP-1 / GIP coagent peptide may be administered with insulin.

Anti-obesity agents known in the art or under study are leptin and fibroblast growth factor 21 (FGF-21), appetite suppressants such as phenethylamine type stimulants, phentermines (optionally fenfluramine or dex) With fenfluramine), diethylpropion (Tenuate®), phendimetrazine (Prelu-2®), Bontril (registered trademark) )), Benzpetamine (Didrex®), sibutramine (Meridia®), Reductil®); Limonabant (Acomplia®), other cannabinoid receptor antagonists; Oxyntomodulin; Fluoxetine hydrochloride (Prozac); Qnexa (topiramite and phentermine), Excalia (bupropion and zonamide) or Contrave (bupropion and naltrexone); Or lipase inhibitors similar to Zenical (Orlistat) or Celtistat (also known as ATL-962), or GT 389-255.

Dose and administration

The extended half-life GLP-1 / GLP coagent peptide may be administered at a weekly dose (total weekly dose) of about 1 mg to about 40 mg. For example, the extended half-life GLP-1 / GLP coagent peptide is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 Mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, About 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 It can be administered in weekly doses of mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg and about 40 mg. In some embodiments, the extended half-life GLP-1 / GLP coagent peptide may be administered at a weekly dose of about 4 mg to about 30 mg. For example, the extended half-life GLP-1 / GLP coagent peptide may be about 4 mg, about 12 mg, about 20 mg or about 30 mg, or about 4 mg to about 20 mg, or about 4 mg to about 12 mg, Or about 6 mg to about 30 mg, or about 6 mg to about 20 mg, or about 6 mg to about 12 mg, or about 8 mg to about 30 mg, or about 8 mg to about 20 mg, or about 12 mg to About 30 mg, or about 12 mg to about 25 mg, or about 12 mg to about 20 mg, or about 10 mg to about 30 mg, or about 10 mg to about 25 mg, or about 10 mg to about 20 mg It may be administered in a dose. In some embodiments, the extended half-life GLP-1 / GLP coagent peptide may be administered at a weekly dose of about 2 mg to about 10 mg. For example, the extended half-life GLP-1 / GLP coagent peptide may be from about 2 mg, about 4 mg, about 6 mg, about 8 mg or about 10 mg, or about 2 mg to about 8 mg, or about 2 mg to It can be administered at a weekly dose of about 6 mg, or about 2 mg to about 4 mg, or about 4 mg to about 10 mg, or about 4 mg to about 8 mg, or about 4 mg to about 6 mg.

The dose given is for an extended half-life GLP-1 / GLP coagent peptide having a molecular weight ranging from about 35 kD to 65 kD, or about 35 kD to about 55 kD, for example about 45 kD. The present invention assumes equimolar capacity for the molecular weight of different peptides. Thus, the present invention assumes a weekly dose of about 23 nmol to about 930 nmol or a weekly dose of about 93 nmol to about 465 nmol. Appropriate weekly dosages are readily calculated. For example, a 12 mg dose for a peptide of about 40-50 kD molecular weight is a molar equivalent of a 6 mg dose for a peptide of about 20-25 kD molecular weight.

The extended half-life GLP-1 / GLP coagent peptide is used every cycle to achieve the desired total weekly dosage (eg, every two weeks, every ten days, once a week, twice a week, three times a week, four times a week, 5 times, 6 times a week or daily). If the desired weekly dose is about 4 mg, for example, the extended half-life GLP-1 / GIP coagent peptide may be administered as 8 mg every 2 weeks, 4 mg once a week, or 2 mg twice a week. . If the desired weekly dose is about 12 mg, for example, the extended half-life GLP-1 / GIP coagent peptide may be administered as 24 mg every two weeks, 12 mg once a week, or 6 mg twice a week. . If the desired weekly dose is about 20 mg, for example, the extended half-life GLP-1 / GIP coagent peptide may be administered as 40 mg every two weeks, 20 mg once a week, or 10 mg twice a week. . If the desired weekly dose is about 30 mg, for example, the extended half-life GLP-1 / GIP coagent peptide may be administered as 60 mg every two weeks, 30 mg once a week, or 15 mg twice a week. .

Equivalent reduced doses (which are reduced proportionally to body surface area or body weight) may be administered to humans, teenagers or children below the average body weight. For example, the adjusted total weekly dose of 12 mg for humans, about half the body surface area of the average adult male, is the total weekly dose of 6 mg. As another example, 12 mg weekly corresponds to about 0.17 mg / kg per week for an average 70 kg male; For an average 70 kg male 20 mg per week is equivalent to about 0.28 mg / kg per week. Thus, for example, the present invention provides about 0.029 mg / kg to about 0.143 mg / kg per week (ie, 2 mg to 10 mg for a 70 kg male), or about 0.057 mg / kg to about 0.28 mg / kg (Ie 4 mg to 20 mg for 70 kg male), or about 0.014 mg / kg to about 0.5 mg / kg per week (ie 1 mg to 35 mg for 70 kg male). Assume administration of coagent peptides.

Pharmaceutical Formulations and Routes of Administration

The extended half-life GLP-1 / GIP coagent peptide may be administered in a pharmaceutical composition comprising an optionally acceptable diluent, carrier, excipient, or mixture thereof. In some embodiments, the pharmaceutical composition is sterile and is, for example, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about Purity level of 96%, at least about 97%, at least about 98% or at least about 99%.

In some embodiments, the pharmaceutical composition comprises about 1 mg / ml to about 50 mg / ml (eg, about 1 mg / ml, about 2 mg / ml, about 3 mg) of an extended half-life GLP-1 / GIP coagent. / Ml, about 4mg / ml, about 5mg / ml, about 6mg / ml, about 7mg / ml, about 8mg / ml, about 9mg / ml, about 10mg / ml, about 11mg / ml , About 12 mg / ml, about 13 mg / ml, about 14 mg / ml about 15 mg / ml, about 16 mg / ml, about 17 mg / ml, about 18 mg / ml, about 19 mg / ml, about 20 Mg / ml, about 21 mg / ml, about 22 mg / ml, about 23 mg / ml, about 24 mg / ml, about 25 mg / ml, about 26 mg / ml, about 27 mg / ml, about 28 mg / Ml, about 29 mg / ml, about 30 mg / ml, about 31 mg / ml, about 32 mg / ml, about 33 mg / ml, about 34 mg / ml about 35 mg / ml, about 36 mg / ml, about 37 mg / ml, about 38 mg / ml, about 39 mg / ml, about 40 mg / ml, about 41 mg / ml, about 42 mg / ml, about 43 mg / ml, about 44 mg / ml, about 45 mg / Ml, about 46 mg / ml, about 47 mg / ml, about 48 mg / ml, about 49 mg / ml and about 50 mg / ml).

In one embodiment, the pharmaceutical composition comprises an aqueous solution that is sterile and optionally stored in various containers. In some embodiments, extended half-life GLP-1 / GIP coagent peptides can be used to prepare preformed solutions prepared for injection. In another embodiment, the pharmaceutical composition comprises lyophilized powder. The pharmaceutical composition may be further packaged as part of a kit comprising a disposable device for administering an extended half-life GLP-1 / GIP coagent peptide to the patient. The container or kit may be labeled for storage at ambient or refrigerated temperatures.

In one embodiment, the kit is equipped with an instrument for administering the extended half-life GLP-1 / GIP coagent peptide to the patient, such as a syringe needle, pen instrument, jet injector or other needleless injector. The kit may alternatively or additionally pre-fill one or more containers, such as vials, tubes, bottles, single or multiple chambers, which optionally contain extended half-life GLP-1 / GIP coagent peptides in frozen form or in aqueous solution. Syringes, cartridges, infusion pumps (external or implantable), jet injectors, prefilled pen instruments and the like. Preferably, the kit will also include instructions for use. In some embodiments, the device of the kit is an aerosol dispensing device wherein the extended half-life GLP-1 / GIP coagent peptide is packaged in an aerosol device. In another embodiment, the kit comprises a syringe and a needle, and in one embodiment, the sterile extended half-life GLP-1 / GIP coagent peptide is prepackaged in a syringe.

Extended half-life GLP-1 / GIP coagent peptide is administered to a patient using any standard route of administration, including intravenous, intraperitoneal, subcutaneous or intramuscular, intrathecal, transdermal, rectal, oral, nasal or inhalation. Can be. For example, extended infusion or parenteral injection over a period of 1, 2, 3, 4, 5, 6, 7, 8, 12 or 24 hours is possible. In some embodiments, the pharmaceutical composition comprising an extended half-life GLP-1 / GIP coagent peptide is administered via parenteral injection, eg, by subcutaneous injection, intravenous injection or intramuscular injection.

In some embodiments, the pharmaceutical composition comprises an extended half-life GLP-1 / GIP coagent peptide or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and / or one or more pharmaceutically Contains acceptable ingredients. Remington's Pharmaceutical Sciences, Sixteenth Edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980), the entirety of which is incorporated by reference, provides a variety of ingredients used to prepare pharmaceutically acceptable compositions. And known techniques for their preparation. Except insofar as any conventional agent is contraindicated with the pharmaceutical composition, its use in the pharmaceutical composition is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

In some embodiments, the pharmaceutically acceptable ingredient is a sugar (eg, glucose, sucrose, trehalose, lactose, fructose, maltose, dextran, glycerine, dextran, meliboise, melezitose, raffinose) , Mannotriose, starchiose, maltose, lactolos, maltulose or iso-maltulose, or combinations of these sugars, sugar alcohols (eg, glycols, glycerol, erythritol, trytol, arabitol , Xylitol, ribitol, mannitol, sorbitol, dulcitol, iditol, isomalt, maltitol, lactitol or glutitol, or a combination of these sugar alcohols), salts (e.g. sodium chloride), emulsifiers or surfactants ( For example, polysorbates such as polyoxyethylene 20 sorbitan monooleate, or other block copolymers of ethylene oxide and propylene oxide), lyoprotectant, and mixtures thereof It is selected from the group consisting of. For example, excipients such as sugars or sugar alcohols, for example, from about 20 mg / ml to about 40 mg / ml, or from 25 to 45 mg / ml, for example. Present at a concentration of 35 mg / ml.

Pharmaceutical compositions can be formulated to achieve physiologically compatible pH, such as from about pH 4 to about pH 11. In some embodiments, the pH of the pharmaceutical composition is, for example, about 7-10. In another embodiment, the pH of the pharmaceutical composition is, for example, about 4 to 7, or 4.5 to about 5.5, for example about 5.

In certain embodiments, the pharmaceutical composition may comprise a buffer to achieve a physiologically suitable pH. Buffers are, for example, phosphate buffers (such as PBS), triethanolamine, Tris, bisine, TAPS, tricine, HEPES, TES, MOPS, PIPES, cacodylate ), MES, acetate, citrate, succinate, histidine or other pharmaceutically acceptable buffers, and the like, may include any compound having the ability to buffer at the desired pH. In certain embodiments, the strength of the buffer is at least 0.5 mM, at least 1 mM, at least 5 mM, at least 10 mM, at least 20 mM, at least 30 mM, at least 40 mM, at least 50 mM, at least 60 mM, at least 70 mM, at least 80 mM, at least 90 mM, at least 100 mM. , At least 120 mM, at least 150 mM or at least 200 mM. In some embodiments, the strength of the buffer is 300 mM or less (e.g. 200mM maximum, 100mM maximum, 90mM maximum, 80mM maximum, 70mM maximum, 60mM maximum, 50mM maximum, 40mM maximum, 30mM maximum, 20mM maximum, 10mM maximum, 5mM maximum, 1mM). For example, the buffer concentration may be about 2 mM to about 100 mM or about 10 mM to about 50 mM.

All descriptions of methods of treatment, pharmaceutical compositions, kits, and other similar embodiments described herein are intended to refer to peptides as including all pharmaceutically acceptable salts, esters, conjugates, or precursors thereof. I understand. Specific embodiments of the invention are further described in the following non-limiting examples that illustrate various characteristics. These examples should not be construed as limiting the scope of the invention as many variations of these embodiments may be practiced and are to be understood in view of the overall disclosure of this specification.

Exemplary embodiments

A. Example Embodiments

In an exemplary embodiment, the extended half-life GLP-1 / GIP coagent peptide is an analog of glucagon (SEQ ID NO: 1) with GIP agonist activity having the following characteristics: GIP activity of interest and GLP-1 To maintain activity;

(a) an amino acid modification at position 1 that confers GIP agonist activity,

(b) a variation selected from the group consisting of:

(i) a lactam bridge between the side chains of amino acids at positions i and i + 4 or between the side chains of amino acids at positions j and j + 3, wherein i is 12, 13, 16, 17, 20 or 24, j is 17) and

(ii) one, two, three or all of the amino acids at positions 16, 20, 21 and 24 of an analog substituted with an α, α-disubstituted amino acid, and

(c) 1 to 10 additional amino acid modifications (eg, 2, 3, 4, 5, 6, 7, 8, 9 or 10).

In any of the exemplary embodiments in this section, the amino acid at position 1 is an amino acid lacking an imidazole side chain, optionally a large aromatic amino acid (eg, Tyr). In any of the exemplary embodiments, the peptide may have a lactam bridge between positions 16 and 20 (eg, between Glu and Lys). In any of the exemplary embodiments, the α, α-disubstituted amino acid can be AIB, and optionally, the amino acid at position 16 is a positively charged amino acid. In any of the exemplary embodiments, the positively charged amino acid is an amino acid of Formula IV:

(IV)

Wherein n is 1 to 7, each of R 1 and R 2 is independently H, C ₁ -C ₁₈ alkyl, (C ₁ -C ₁₈ alkyl) OH, (C ₁ -C ₁₈ alkyl) NH _2, (C ₁ -C ₁₈ alkyl) SH, (C ₀ -C ₄ alkyl) (C ₃ -C ₆ ) cycloalkyl, (C ₀ -C ₄ alkyl) (C ₂ -C ₅ heterocyclic), (C ₀ -C ₄ Alkyl) (C ₆ -C ₁₀ aryl) R ₇ and (C ₁ -C ₄ alkyl) (C ₃ -C ₉ heteroaryl), wherein R ₇ is H or OH, an amino acid of formula IV The side chain of the free amino group; Optionally Homo Lys, Lys, Orn or 2,4-diaminobutyric acid (Dab).

In some exemplary embodiments, the extended half-life GLP-1 / GIP coagent peptide is an analog of glucagon (SEQ ID NO: 1) with GIP agonist activity having the following properties; An extension of 1 to 21 amino acids C-terminus to an acrylated amino acid at position 10 or an amino acid at position 29 comprising an acrylated amino acid; Further optionally (i) amino acid modification at position 1 to confer GIP agonist activity and (ii) (A) between the side chains of amino acids at positions i and i + 4 or at positions j and j + Lactam bridges between the side chains of the amino acid at position 3, wherein i is 12, 13, 16, 17, 20 or 24, and j is 17; And (B) at least one or both of one, two, three or all of the amino acids at positions 16, 20, 21 and 24 of the analog are substituted with an α, α-disubstituted amino acid; (iii) up to 10 additional amino acid modifications (eg, 2, 3, 4, 5, 6, 7, 8, 9 or 10). Optionally, the amino acid at position 16 is a positively charged amino acid.

In any of the exemplary embodiments, the peptide also includes an amino acid modification at one, two or both of positions 27, 28, and 29, eg, where (a) Met at position 27 is large An aliphatic amino acid, optionally substituted with Leu, or (b) Asn at position 28 is substituted with a small aliphatic amino acid, optionally Ala, or (c) Thr at position 29 is substituted with a small aliphatic amino acid, optionally Gly Or (d) a combination of both or both of (a), (b) and (c) above. The amino acid at position 2 is optionally a DPP-IV protecting amino acid such as alpha, an alpha disubstituted amino acid (eg AIB). In any of the exemplary embodiments, the peptide has a C-terminal amide or ester. In any of the exemplary embodiments, the peptide comprises an extension of 1 to 21 amino acids C-terminal of amino acid at position 29, such as GPSSGAPPPS; Optionally 1 to 6 amino acids of its extension are positively charged amino acids.

B. Exemplary Embodiments

In some exemplary embodiments, the extended half-life GLP-1 / GIP coagent peptide is an analog of glucagon (SEQ ID NO: 1) with GIP agonist activity, having the following characteristics: an acrylated amino acid at position 10, Or an extension of 1 to 21 amino acids C-terminal to the amino acid at position 29 comprising an acrylated amino acid; Optionally, maintaining the desired GIP activity and GLP-1 activity; (i) amino acid modification at position 1 that confers GIP agonist activity, and (ii) (A) between side chains of amino acids at positions i and i + 4, or at positions j and j + 3 Lactam bridges between the side chains of amino acids in, where i is 12, 13, 16, 17, 20 or 24 and j is 17; And (B) at least one or both of one, two, three or all of the amino acids at positions 16, 20, 21 and 24 of the analog are substituted with an α, α-disubstituted amino acid; And (iii) up to 10 additional amino acid modifications (eg, 2, 3, 4, 5, 6, 7, 8, 9 or 10). Optionally, the amino acid at position 16 is a positively charged amino acid.

In any of the exemplary embodiments, the peptide also includes an amino acid modification at one, two or both of positions 27, 28 and 29, eg, wherein (a) Met at position 27 is A large aliphatic amino acid, optionally substituted with Leu, (b) an Asn at position 28 is substituted with a small aliphatic amino acid, optionally Ala, or (c) a Thr at position 29 is a small aliphatic amino acid, optionally Gly Or (d) a combination of both or both of (a), (b) and (c) above. The amino acid at position 2 is optionally a DPP-IV protecting amino acid such as alpha, an alpha disubstituted amino acid (eg AIB). In any of the exemplary embodiments, the peptide has a C-terminal amide or ester. In any of the exemplary embodiments, the peptide comprises an extension of 1 to 21 amino acids C-terminal to amino acid at position 29, such as GPSSGAPPPS; Optionally 1 to 6 amino acids of the extension are positively charged amino acids.

In some exemplary embodiments, the extended half-life GLP-1 / GIP coagent peptide is an analog of glucagon (SEQ ID NO: 1) with GIP agonist activity, having the following characteristics: GIP activity and GLP− of interest. 1 to maintain activity; (a) an amino acid modification at position 1 that is a substitution of His with an amino acid lacking an imidazole side chain that confers GIP agonist activity, (b) side chains of amino acids at positions i and i + 4 Lactam bridges between the liver or the side chains of amino acids at position j and at position j + 3, where i is 12, 13, 16, 17, 20 or 24, and j is 17, (c) , Amino acid modifications at one, two or both of positions 28 and 29, and (d) 1 to 9 (eg, up to 2, 3, 4, 5, 6, 7, 8, 9 or 10) Further amino acid modifications.

In any of the exemplary embodiments in this section, the amino acid at position 1 is an amino acid lacking an imidazole side chain, optionally a large aromatic amino acid (eg, Tyr). In any of the exemplary embodiments, the peptide may have a lactam bridge between the amino acid at position 16 and the amino acid at position 20 (eg, between Glu and Lys). In any of the exemplary embodiments, the peptide may also be selected from (a) a high aliphatic amino acid of Met at position 27, optionally Leu, or (b) a small aliphatic amino acid of Asn at position 28, selective To Ala, or (c) a Thr is substituted at position 29 with a small aliphatic amino acid, optionally Gly. The amino acid at position 2 is optionally a DPP-IV protecting amino acid such as alpha, an alpha disubstituted amino acid (eg AIB). In any of the exemplary embodiments, the peptide has a C-terminal amide or ester. In any of the exemplary embodiments, the peptide comprises an extension of 1 to 21 amino acids C-terminal to amino acid at position 29, such as GPSSGAPPPS; Optionally 1 to 6 amino acids of the extension are positively charged amino acids.

In some exemplary embodiments, the extended half-life GLP-1 / GIP coagent peptide is an analog of glucagon (SEQ ID NO: 1) with GIP agonist activity, having the following characteristics: GIP activity and GLP− of interest. 1 to maintain activity; (a) amino acid modification at position 1 that confers GIP agonist activity, (b) one, two, three, or all of the amino acids at positions 16, 20, 21, and 24 of the analog are α, α-disubstituted Substituted amino acids, such as AIB, (c) amino acid modifications at one, two or both of positions 27, 28 and 29, and (d) 1 to 9 (eg 2, 3, 4) , Up to 5, 6, 7, 8, 9) further amino acid modifications.

In any of the exemplary embodiments in this section, the amino acid at position 1 is an amino acid lacking an imidazole side chain, optionally a large aromatic amino acid (eg, Tyr). In any of the exemplary embodiments, the peptide may have a lactam bridge between the amino acid at position 16 and the amino acid at position 20 (eg, between Glu and Lys). In any of the exemplary embodiments, the peptide may also be selected from (a) a substitution of a large aliphatic amino acid for Met at position 27, optionally Leu, or (b) an aliphatic amino acid with a low Asn position at position 28, selective To Ala, or (c) a Thr is substituted at position 29 with a small aliphatic amino acid, optionally Gly. The amino acid at position 2 is optionally a DPP-IV protecting amino acid such as alpha, an alpha disubstituted amino acid (eg AIB). In any of the exemplary embodiments, the peptide has a C-terminal amide or ester. In any of the exemplary embodiments, the peptide comprises an extension of 1 to 21 amino acids C-terminal to amino acid at position 29, such as GPSSGAPPPS; Optionally 1 to 6 amino acids of the extension are positively charged amino acids.

In some exemplary embodiments, the extended half-life GLP-1 / GIP coagent peptide is an analog of glucagon (SEQ ID NO: 1) with GIP agonist activity, having the following characteristics: GIP activity and GLP− of interest. 1 to maintain activity; (a) an amino acid modification at position 1 that confers GIP agonist activity, (b) at position 16, an amino acid of formula IV:

(IV)

Wherein n is 1 to 7 and each of R 1 and R 2 is independently H, C ₁ -C ₁₈ alkyl, (C ₁ -C ₁₈ alkyl) OH, (C ₁ -C ₁₈ alkyl) NH _2, (C ₁ -C ₁₈ alkyl) SH, (C ₀ -C ₄ alkyl) (C ₃ -C ₆ ) cycloalkyl, (C ₀ -C ₄ alkyl) (C ₂ -C ₅ heterocyclic), (C ₀ -C ₄ alkyl) (C ₆ -C ₁₀ aryl) R ₇ and (C ₁ -C ₄ alkyl) (C ₃ -C ₉ heteroaryl), wherein R ₇ is H or OH, and The side chains of amino acids include free amino groups), (c) alpha, alpha-disubstituted amino acids at position 20, such as AIB, (d) at one, two or both of positions 27, 28 and 29 Amino acid modifications, and (e) one to nine further amino acid modifications (eg, up to 2, 3, 4, 5, 6, 7, 8, 9).

In any of the exemplary embodiments in this section, the amino acid at position 1 is an amino acid lacking an imidazole side chain, optionally a large aromatic amino acid (eg, Tyr). In any of the exemplary embodiments, the peptide may also be selected from (a) a substitution of a large aliphatic amino acid for Met at position 27, optionally Leu, or (b) an aliphatic amino acid with a low Asn position at position 28, selective To Ala, or (c) a Thr is substituted at position 29 with a small aliphatic amino acid, optionally Gly. In any of the exemplary embodiments, the amino acid of formula IV in (b) is homo Lys, Lys, Orn or 2,4-diaminobutyric acid (Dab). The amino acid at position 2 is optionally a DPP-IV protecting amino acid such as alpha, an alpha disubstituted amino acid (eg AIB). In any of the exemplary embodiments, the peptide has a C-terminal amide or ester. In any of the exemplary embodiments, the peptide comprises an extension of 1 to 21 amino acids C-terminal to amino acid at position 29, such as GPSSGAPPPS; Optionally 1 to 6 amino acids of the extension are positively charged amino acids.

Other optional variations include:

(a) Ser at position 2 substituted with D-Ser, Ala, D-Ala, Gly, N-methyl-Ser, AIB, Val or α-amino-N-butyric acid;

(a) Tyr at position 10 substituted with Trp, Lys, Orn, Glu, Phe or Val;

(b) a chain of acyl groups for Lys at position 10;

(c) Lys at position 12 substituted with Arg or Ile;

(d) Ser at position 16 substituted with Glu, Gln, homoglutamic acid, homocysteic acid, Thr, Gly or AIB;

(e) Arg at position 17 substituted with Gln;

(f) Arg at position 18 substituted with Ala, Ser, Thr or Gly;

(g) Gln at position 20 substituted with Ser, Thr, Ala, Lys, citrulline, Arg, Orn or AIB;

(h) Asp at position 21 substituted with Glu, homoglutamic acid, homocysteic acid;

(i) Val at position 23 substituted with Ile;

(j) Gln at position 24 substituted with Asn, Ser, Thr, Ala or AIB; And

(k) conservative substitutions in any of positions 2, 5, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 24, 27, 28, and 29 .

 C. Exemplary Embodiments

 In an exemplary embodiment, the extended half-life GLP-1 / GIP coagent peptide is an analog of glucagon (SEQ ID NO: 1) with GIP agonist activity, including: GIP activity and GLP-1 activity of interest To maintain;

(a) an amino acid comprising the imidazole side chain at position 1,

(b) at position 16, amino acid of formula IV:

(IV)

(Wherein n is 1 to 7, each of R1 and R2 is independently H, C1-C18 alkyl, (C1-C18 alkyl) OH, (C1-C18 alkyl) NH2, (C1-C18 alkyl) SH, ( C0-C4 alkyl) (C3-C6) cycloalkyl, (C0-C4 alkyl) (C2-C5 heterocyclic), (C0-C4 alkyl) (C6-C10 aryl) R7 and (C1-C4 alkyl) (C3 -C9 heteroaryl) wherein R7 is H or OH and the side chain of the amino acid of formula IV comprises a free amino group),

(c) an α, α-disubstituted amino acid at position 20,

(d) up to 10 additional amino acid modifications to SEQ ID NO: 1 (eg, up to 2, 3, 4, 5, 6, 7, 8, 9 or 10).

In any of the exemplary embodiments in this section, the amino acid at position 1 may be His or His derivatives. In any of the exemplary embodiments, the amino acid of formula (IV) in (b) can be homo Lys, Lys, Orn, or 2,4-diaminobutyric acid (Dab). In any of the exemplary embodiments, the α, α-disubstituted amino acids include R 1 and R 2, each of which is bonded to an alpha carbon, wherein each of R 1 and R 2 is independently hydroxyl, amide, thiol, Selected from the group consisting of C1-C4 alkyl, optionally substituted with halo, or R 1 and R 2 together with the alpha carbon to which they are attached form a ring; Optionally AIB. The amino acid at position 2 is optionally a DPP-IV protecting amino acid such as alpha, an alpha disubstituted amino acid (eg AIB). In any of the exemplary embodiments, the peptide has a C-terminal amide or ester. Optionally the peptide comprises an extension of 1 to 21 amino acids C-terminal to amino acid at position 29, such as GPSSGAPPPS, or a conservatively substituted sequence thereof.

 D. Exemplary Embodiments

In an exemplary embodiment, the extended half-life GLP-1 / GIP coagent peptide of the present invention comprises (i) an imidazole side chain at position 1 that maintains the desired GIP activity and GLP-1 activity. Amino acids, (ii) a DPP-IV protecting amino acid at position 2, (iii) an optionally acrylated or alkylated amino acid at any of positions 9, 10, 12, 16, 20 or 37 to 43, wherein optionally acyl Or an alkyl group is linked to an amino acid through a spacer); (iv) an alpha helix that stabilizes amino acids at one or more of positions 16-21, and (v) up to 10 (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or about native glucagon) or Analogues of natural glucagon, up to 10 additional amino acid modifications).

In any of the exemplary embodiments in this section, the amino acid at position 1 may be His or His derivatives. In any of the exemplary embodiments, the amino acid at position 2 is an α, α-disubstituted amino acid. In any of the exemplary embodiments, the α, α-disubstituted amino acids include R 1 and R 2, each bound to an alpha carbon, wherein each of R 1 and R 2 is independently hydroxyl, amide, thiol, halo Optionally substituted C1-C4 alkyl, or R1 and R2 together with the alpha carbon attached to them form a ring; Optionally AIB or ACPC. In any of the exemplary embodiments, the glucagon analogue includes alpha helix stabilizing amino acids, such as alpha, alpha disubstituted amino acids, at position 20, and the like.

 In any of the exemplary embodiments, the peptide comprises an extension of 1 to 21 amino acids C-terminal to the amino acid at position 29, which is an amino acid sequence forming a Trp cage structure: optionally GPSSGAPPPS, or Conservatively substituted sequences thereof; Also optionally comprises at least one charged amino acid.

Example

Example 1: Extended half-life The GLP-1 / GIP coagent peptide was well tolerated with an extended half-life of about 5 days.

Phase 1, randomized, placebo-controlled, sequential, single-elevation, two-cycle, study shows safety, tolerance, pharmacokinetic (PK) and pharmacodynamic (PD) of extended half-life GLP-1 / GIP coagent peptides. It was performed in healthy male subjects to assess the characteristics. Healthy, generally healthy, with a body mass index of 20 kg / m 2 to 30 kg / m 2, based on medical history, physical examination, ECG, and routine laboratory tests (eg, blood, chemistry, hematology, urine forceps, and drug screens) Adult male subjects (ages of about 18-55 years old) were selected for this study. The extended half-life GLP-1 / GIP coagent peptide tested in all examples was SEQ ID NO: 153.

Subjects were randomly assigned to cohorts. Cohorts 1, 2, 3, 4, 5 and 6 each consisted of 6 patients, each with 0.1 mg, 0.3 mg, 1 mg, 2 mg, 4 mg of extended half-life GLP-1 / GIP coagent peptide, respectively. And 8 mg and two patients received placebo. Cohorts 1 ', 2', and 3 'each consisted of 6 patients, each with 16 mg, 24 mg, and 32 mg of extended half-life GLP-1 / GIP coagent peptide, and 2 patients with placebo Was supplied.

After at least 10 hours of fasting overnight, subjects received a single dose of study drug or placebo as a subcutaneous (SC) injection in the abdomen. Blood samples were collected for fasting insulin, glucose and glucagon levels on days 1 and 2, 3, 4, 5, 6 and 7 before dosing (ie within 30 minutes prior to dosing). Plasma samples for pharmacokinetic analysis were collected on day 1 and on days 2, 3, 4, 5, 6, 7, 14, 28 and 35, and at 0.5, 1, 2, 4, 8 and 12 hours post-dose. . Subjects were monitored for 35 days for side effects, body weight and vital signs.

During the study, plasma AUC _0-τ , AUC _0-infinity and C _maximum increased with the dose of study drug and apparent t _1/2 was approximately 5 days. The extended half-life GLP-1 / GIP coagent peptide was considered to be dose proportional for both AUC and C _max at doses ranging from 0.1 mg to 32 mg. At the 0.1 mg dose, mean C _maximum was 183 pM and AUC (AUC _0-144 ) was 12,349 pM · hr. At the 8 mg dose, mean C _max was 12,989 pM and AUC (AUC _0-144 ) was 1,382,376 pM · hr. At the 32 mg dose, mean C _maximum was 54.8 nM and AUC (AUC _0-final ) 12,582 nM · hr.

The time for the maximum observed plasma concentration (T _max ) was that of subjects administered higher concentrations of extended half-life GLP-1 / GIP coagent peptide (56.0 hours at 24 mg; 80.0 hours at 32 mg). Compared to subjects administered with the lowest amount of extended half-life GLP-1 / GIP coagent peptide (112.5 hours at 16 mg).

The absolute bioavailability of the extended half-life GLP-1 / GIP coagent peptide was 100% and its accumulation index was 1.7-2 fold. Treatment was generally safe and well tolerated.

As expected in healthy subjects, no dose-related trends were observed for fasting insulin, glucose and glucagon levels. However, the treatment group tended to have a numerically greater reduction from baseline in mean daily fasting glucose levels on day 7, compared to the placebo group (placebo: 78.7 mg / dL; 16 mg dose: 76.5 mg). 24 mg dose: 72.7 mg / dL 32 mg dose: 71.7 mg / dL). These reductions were within the normal range for healthy subjects in the study, but the degree of attenuation in diabetic patients is considered clinically important.

Example 2: Extended half-life GLP-1 / GIP coagent peptide increased insulin secretion in a dose dependent manner

 Phase 1, randomized, placebo-controlled, positive-controlled 2-sector studies were conducted to assess the effects of dose ranges on beta cell response to glucose loading and to assess the effects of these doses on gastric emptying. And female subjects. Beta cell function was assessed by calculation of prehepatic insulin secretion in response to stepwise glucose infusion. Gastric emptying was assessed by measurement of the plasma appearance of acetaminophen ingested.

Subjects in Division 1 (cohort 1) received two subcutaneous (SC) injections in the abdomen on the first day at two hour intervals, and then on day 2, two 5 μg subcutaneous doses of Amylin Pharmaceuticals in the abdomen ( SC) received injections at 2 hour intervals (10 μg total). During Division 2, subjects in Cohort 2 received a placebo on Day 1 followed by an 8 mg extended half-life GLP-1 / GIP coagent peptide on Day 2. Subjects in Cohort 3 received placebo on day 1 and then received 4 mg of extended half-life GLP-1 / GIP coagent peptide on day 2. Subjects in Cohort 4 received 16 mg of extended half-life GLP-1 / GIP coagent peptide on day 2 after receiving placebo on day 1.

Division 1 (cohort 1)

One day after fasting overnight for up to 10 hours, subjects in Division 1 (Cohort 1) received a single SC injection of placebo at −120 minutes. Body weight was measured at -120 minutes to calculate stepwise glucose infusion. Glucose, C-peptide, insulin, and blood samples for safety laboratory tests were taken at -120, -15, and -10 minutes. At -10 minutes, subjects received 1000 mg acetaminophen elixir with 240 ml water. At 0 minutes, a staged infusion of glucose (20% dextrose) was initiated, a second SC injection of placebo was administered, and blood samples for glucose, C-peptide, insulin, and safety laboratory tests were taken. Glucose was injected at a rate of 2, 4, 6, 8 and 12 mg / kg / min for a total of 2.5 hours. Each glucose infusion level was maintained for 30 minutes. Blood samples for glucose, C-peptide and insulin were taken again at 10, 20 and 30 minutes for each 30 minute infusion period. Blood samples for plasma acetaminophen concentrations were taken at -10, 30, 60, 90, 120, 150, 180, 210, 240, 300 and 480 minutes. 12-lead ECG was performed at 210 minutes.

Two days after overnight fasting up to 10 hours, subjects in Cohort 1 received 5 μg of Byetta by SC injection at −120 minutes. Blood samples for glucose, C-peptide and insulin were taken at -120, -15 and -10 minutes. At −10 minutes, subjects ingested 1000 mg of acetaminophen elixir with 240 ml of water. At 0 minutes, a staged infusion of glucose (20% dextrose) commenced, subjects received a second SC injection of 5 μg of Byetta, and taken blood samples for C-peptide, insulin, glucose and safety laboratory tests It was. Glucose was injected for a total of 2.5 hours at rates of 2, 4, 6, 8 and 12 mg / kg / minute. Each level of glucose infusion was maintained for 30 minutes. Blood samples for Bayeta concentrations were taken at 0, 60 and 120 minutes. Blood samples for glucose, C-peptide and insulin were taken at 10, 20 and 30 minutes for each 30 minute infusion period. Blood samples for plasma acetaminophen concentrations were taken at −10 minutes, 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes, 210 minutes, 240 minutes, 300 minutes and 480 minutes. 12-lead ECG was performed at 210 minutes.

 On day 3, blood samples were collected for safety laboratory tests and 12-lead ECGs were performed. Subjects in Cohort 1 were released from the site of irradiation on the 3rd evening.

2 divisions (cohort 2 to cohort 4)

On day 1 after overnight fasting up to 10 hours, subjects in Division 2 (Cohorts 2 to 4) received a single SC injection of placebo at -120 minutes. Body weight was measured at -120 minutes to calculate stepwise glucose infusion. Glucose, C-peptide, insulin, and blood samples for safety laboratory tests were taken at -15 and -10 minutes. At −10 minutes, subjects ingested 1000 mg of acetaminophen elixir with 240 ml of water. At 0 minutes, a staged infusion of glucose (20% dextrose) was initiated and blood samples for glucose, C-peptide and insulin were taken. Glucose was injected for a total of 2.5 hours at rates of 2, 4, 6, 8 and 12 mg / kg / minute. Each level of glucose infusion was maintained for 30 minutes. Blood samples for glucose, C-peptide and insulin were taken again at 10, 20 and 30 minutes for each 30 minute infusion period. Blood samples for plasma acetaminophen concentrations were taken at −10 minutes, 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes, 210 minutes, 240 minutes, 300 minutes and 480 minutes. 12-lead ECG was performed at 210 minutes.

Two days after overnight fasting up to 10 hours, blood samples for glucose, C-peptide and insulin were taken at −10 minutes. Subjects received an injection of half-life GLP-1 / GIP coagent peptide extended at 0 minutes. Subjects in cohort 2 received 8 mg of extended half-life GLP-1 / GIP coagent peptide, subjects in cohort 3 received 4 mg of extended half-life GLP-1 / GIP coagent peptide, subjects in cohort 4 extended 16 mg of the half-life GLP-1 / GIP coagent peptide was given. At 0 minutes, blood samples were taken for extended half-life GLP-1 / GIP coagent peptide concentrations, C-peptides, insulin, glucose, and safety laboratory tests. 12-lead ECG was performed at 210 minutes.

On days 3 and 4, blood samples were collected for safety laboratory tests.

5 days after overnight fasting of up to 10 hours (72 hours after extended half-life GLP-1 / GIP coagent peptide administration), blood samples for glucose, C-peptide and insulin are taken at -15 and -10 minutes It was. At −10 minutes, subjects ingested 1000 mg of acetaminophen elixir with 240 ml of water. At 0 minutes, staged infusion of glucose (20% dextrose) was initiated and blood samples were taken for glucose, C-peptide, insulin, safety laboratory tests, and extended half-life GLP-1 / GIP coagent peptide concentrations. . Glucose was injected for a total of 2.5 hours at rates of 2, 4, 6, 8 and 12 mg / kg / min. Each level of glucose infusion was maintained for 30 minutes. Blood samples for glucose, C-peptide and insulin were taken at 10, 20 and 30 minutes for each 30 minute infusion period. Blood samples for plasma acetaminophen concentrations were taken at −10 minutes, 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, 180 minutes, 210 minutes, 240 minutes, 300 minutes and 480 minutes. Blood samples for extended half-life GLP-1 / GIP coagent peptide concentrations were taken at 120 minutes. 12-lead ECG was performed at 210 minutes.

Subjects in Cohort 2 to Cohort 4 remained confined to the study site by evening of the 7th. On days 6 and 7, blood samples were collected for safety laboratory tests. On day 7, 12-lead ECG was performed.

result

During Division 1, an increase in glucose dose dependency of insulin secretion rate after Bayeta treatment was observed with an increase in each glucose infusion rate. Treatment comparison of the mean-squares (LS) mean change in insulin secretion rate between placebo and Byetta at each glucose infusion rate (0.12 μIU / ml per mg / dL) was statistically significant (p <0.0001) .

Treatment with Byetta was associated with a significant delay in acetaminophen uptake compared to placebo. Subjects had a shift of T _max and lower C _max between 30 and 210 minutes after treatment with Byetta. This result is consistent with Bayeta's published effects on gastric emissions.

During section 2, a dose dependent, dose proportional increase in insulin secretion rate (ISR) was observed after treatment with extended half-life GLP-1 / GIP coagent peptide compared to placebo. At the maximum dose (16 mg), insulin secretion rate was increased by approximately 44% (p = 0.001). Rate of glucose infusion between placebo and 16 mg extended half-life GLP-1 / GIP coagent peptide group, rate of glucose infusion between placebo and 8 mg extended half-life GLP-1 / GIP coagent peptide group (0.04 μIU) / Placebo and 4 mg extended half-life GLP-1 / GIP co-agent peptide group liver glucose infusion rate (0.03 μIU / mL), extended half-life GLP-1 / GIP co-agent peptide 8 mg group and 16 mg liver glucose Infusion rate (0.03 μIU mL perpermg / dL), prolonged half-life GLP-1 / GIP coagent peptide 4 mg and 16 mg glucose infusion rate (0.04 μIU / mL perpermg / dL), and extended half-life GLP Treatment comparison of the mean squared (LS) mean change in insulin secretion rate at the glucose infusion rate (0.01 μμIU / mL per mg / dL) between the -1 / GIP coagent Peptide # 4 mg and 8 mg group was statistically significant ( P <0.001, p <0.001 and p <0.001, p <0.0001, p <0.0001 and p = 0.0067 respectively). This result is illustrated in FIG. 1. All extended half-life GLP-1 / GIP coagent peptide dose groups showed higher insulin secretion rates than the placebo group. The extended half-life GLP-1 / GIP coagent peptide 16 mg group was more consistent than the other two extended half-life GLP-1 / GIP coagent peptide treatment groups at 4 μg / kg / min to 12 μg / kg / min glucose infusion rate. Very high insulin secretion rate.

In general, all extended half-life GLP-1 / GIP coagent peptide dose groups had lower glucose levels than the placebo group at all glucose infusion rates. In general, lower mean glucose values were observed at each glucose infusion rate of the 16 mg group of extended half-life GLP-1 / GIP coagent peptide compared to the other extended half-life GLP-1 / GIP coagent peptide dose groups. For the 16 mg and 8 mg groups with extended half-life GLP-1 / GIP coagent peptide, there was no increase in glucose levels between the 8 μg / kg / min infusion rate and the 12 mg / kg / min infusion rate. 2A illustrates the comparison of placebo with 4 mg dose of extended half-life GLP-1 / GIP coagent peptide. 2B illustrates the results of comparing the 8 mg dose of extended half-life GLP-1 / GIP coagent peptide with placebo.

Glucose infusion rate between placebo and 16 mg group of extended half-life GLP-1 / GIP coagent peptide (0.43 μIU / ml per mg / dL), glucose injection between placebo and 8 mg group of extended half-life GLP-1 / GIP coagent peptide Rate (0.35 μIU / mL per mg / dL), glucose infusion rate (0.27 μIU / mL per mg / dL) between placebo and 4 mg group of extended half-life GLP-1 / GIP coagent peptide, extended half-life GLP-1 / Glucose infusion rate (0.08 μIU / mL per mg / dL) between GIP coagent peptide group 8 mg and 16 mg, glucose infusion rate between 4 mg group and 16 mg group with extended half-life GLP-1 / GIP coagent peptide (mg 0.17 μIU / mL / dL, and LS mean change in insulin at glucose infusion rate (0.09 μIU / mL / mg / dL) between extended and half-life GLP-1 / GIP coagent peptide groups 4 mg and 8 mg. The comparison was statistically significant (p <0.0001, p <0.0001, p <0.0001, p = 0.0316, p <0.0001 and p = 0.0251, respectively).

Consistent with the observed increase in insulin secretion rate, an increase in dose dependent, dose proportional, C-peptide levels was observed after treatment with extended half-life GLP-1 / GIP coagent peptide compared to placebo (FIG. 3). . Glucose injection rate between placebo and 16 mg group of extended half-life GLP-1 / GIP coagent peptide (0.05 ng / ml per mg / dL), glucose injection between placebo and 8 mg group of extended half-life GLP-1 / GIP coagent peptide Rate (0.03 ng / ml per mg / dL), glucose infusion rate (0.02 ng / ml per mg / dL) between placebo and 4 mg group of extended half-life GLP-1 / GIP coagent peptide, extended half-life GLP-1 / Glucose infusion rate (0.02 ng / ml per mg / dL) between GIP coagent peptide 8 mg group and 16 mg group, glucose infusion rate between 4 mg group and 16 mg group with extended half-life GLP-1 / GIP coagent peptide 0.03 ng / ml / d), and treatment comparison of LS mean change of C peptide at glucose infusion rate (0.01 ng / ml) between 4 mg group and 8 mg group with extended half-life GLP-1 / GIP coagent peptide Statistically significant (p <0.0001, p <0.0001, p <0.0001, p <0.0001, p <0.0001 and p = 0.0055, respectively). In general, an increase in glucose dose dependency of C-peptides after treatment with extended half-life GLP-1 / GIP coagent peptides was observed with each increase in glucose infusion rate.

The extended half-life GLP-1 / GIP coagent peptide was not associated with a significant delay in absorption of acetaminophen. At higher doses of the extended half-life GLP-1 / GIP coagent peptide, there was a tendency towards lower C _max , but T _max was not significantly different from placebo and total acetaminophen absorbed (AUC _{0-4 hours} ) was also There was no significant difference from placebo. Figure 4 compares the extended half-life GLP-1 / GIP coagent peptide and Byetta (AUC _{0-4 hours} ) at 4 mg, 8 mg and 16 mg doses. Extended half-life GLP-1 / GIP coagent peptides do not delay gastric emptying at doses that increase insulin secretion in response to glucose infusion.

Doses of 4 mg, 8 mg and 16 mg of extended half-life GLP-1 / GIP coagent peptide increased insulin secretion in a dose dependent manner during stepwise glucose infusion without effect on gastric emptying. Patients administered the 4 mg dose of extended half-life GLP-1 / GIP coagent peptide expressed on average increased insulin secretion rate, increased C-peptide levels and lower glucose levels in response to glucose infusion.

Example 3: Effect of Extended Half-Life GLP-1 / GIP Coagent Peptides in Patients with Type II Diabetes

Randomized, placebo-controlled, sequential, multistage elevated dose studies have HbA _1c levels that are at least about 6.5% but less than or equal to 10.5% and are diagnosed with type 2 diabetes and on stable metformin monotherapy (ie, at least about 2 before the study). Male and female patients (age between 18 and 70 years old) who are at the same dose for months). Other criteria include fasting glucose levels of 110 mg / dL to 200 mg / dL, body mass index 27 kg / m 2 to 40 kg / m 2, systolic blood pressure less than 155 mmHg, diastolic blood pressure less than 95 mmHg, and significant history of other diseases or complications. It includes things you don't have.

Patients are randomly assigned to 4 cohorts. Cohort 1 consists of eight patients receiving 4 mg of extended half-life GLP-1 / GIP coagent peptide and two patients receiving placebo. Cohort 2 consists of eight patients receiving 12 mg of extended half-life GLP-1 / GIP coagent peptide and two patients receiving placebo. Cohort 3 consists of eight patients receiving 20 mg of extended half-life GLP-1 / GIP coagent peptide and two patients receiving placebo. Cohort 4 consists of eight patients receiving 30 mg of extended half-life GLP-1 / GIP coagent peptide and two patients receiving placebo.

Patients receive a total of six SC doses once per week of study drug on days 1, 8, 15, 22, 29 and 36. Meal tolerance tests are performed on days 1, 4, 36, 43 and 50. On these dates, after fasting overnight (ie 10 hours), blood samples are obtained for fasting insulin, glucose, glucagon and C-peptide. Patients will have Sustacal breakfast (16 ounces) over about 10 minutes. Blood samples for insulin, glucose, glucagon and C-peptide are taken again 10 minutes after the initiation of sustacal ingestion, and then continued over a 3 hour period after the end of the ingestion. After the meal load test, patients receive a single SC injection of study drug (except days 4 and 43). Continuous time blood samples for plasma PK are obtained before and after injection of study drug.

Home capillary glucose values are recorded at least six times per week. Throughout this study, chemical analytes (e.g. alkaline phosphatase, amylase, sodium, potassium, total protein, calcium, chloride, bicarbonate, glucose, creatine phosphokinase, lactate dehydrogenase, alanine aminotransferase, albumin, asparta) Tate aminotransferase, total / direct / indirect bilirubin, urea nitrogen in the blood, creatine, hematology analytes (eg hemoglobin, hematocrit, erythrocyte count, leukocyte count and differential mean hemoglobin concentration, reticulocyte count, mean blood cell) Volume, mean blood cell hemoglobin, platelet count, lipids (eg, low density lipoprotein cholesterol, high density lipoprotein cholesterol, total cholesterol, triglycerides), coagulation (eg, activated partial thromboplastin time, prothrombin time, international Normal ratio), analytes (eg, pH, specific gravity, protein, glucose, Analytes are measured periodically, including leukocyte esterases, bilirubin, blood, nitrates, ketones), and follicle stimulating hormone.

Pharmacokinetic variables are evaluated. In addition, the pharmacodynamic variables evaluated include insulin, glucose, glucagon, C-peptide, HbA _1c and fructosamine. Administration of an extended half-life GLP-1 / GIP coagent peptide is expected to result in a biological response of one or more of these parameters. For example, increased insulin levels, decreased glucose levels, increased C-peptide levels, decreased HbA _1c levels, decreased fructosamine levels, and combinations thereof.

All documents, including publications, patent applications, and patent publications cited herein, are hereby expressly incorporated by reference in their entirety and are hereby incorporated by reference in their entirety as if described in full herein.

The use of a singular form and the like in the context of describing the invention (particularly in the context of the following claims) is intended to include both the singular and the plural unless the context clearly indicates otherwise or contradicts the context. Should be interpreted. The terms "comprising", "having", "comprising" and "containing" are to be interpreted as open-termining terms (ie, meaning "including but not limited to") unless stated otherwise. do.

Citations of numerical ranges herein are merely intended to provide an abbreviated method of individually referring to each individual value and each endpoint falling within that range unless otherwise indicated, each individual value and Endpoints are incorporated into the specification as if individually recited herein.

All methods described herein may be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all embodiments or exemplary terms (eg, "such as" and the like) provided herein is intended to clarify the invention further and is limited to the scope of the invention unless otherwise claimed. It is not raised. No term in this specification should be construed as indicating any non-claimed element to the same extent as is essential to the practice of the invention.

Preferred embodiments of the invention are described herein, including the best mode known to the inventors for carrying out the invention. Modifications of these preferred embodiments will become apparent to those skilled in the art upon reading the above description. The inventors expect skilled artisans to employ such variations as needed, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, the invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination in all possible variations of the foregoing elements is encompassed by the present invention unless otherwise indicated herein or otherwise clearly contradicted by context.

                         SEQUENCE LISTING <110> MARCADIA BIOTECH, INC.   <120> METHODS FOR TREATING METABOLIC DISORDERS AND OBESITY WITH GIP AND         GLP-1 RECEPTOR-ACTIVE GLUCAGON-BASED PEPTIDES <130> WO2012 / 088379 <140> PCT / US2011 / 066739 <141> 2011-12-22 <150> 61 / 500,229 <151> 2011-06-23 <150> 61 / 426,338 <151> 2010-12-22 <160> 413 <170> PatentIn version 2.0 <210> 1 <211> 29 <212> PRT <213> Homo sapiens <220> <221> MISC_FEATURE <223> Wild type glucagon <400> 1 His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr             20 25 <210> 2 <211> 31 <212> PRT <213> Homo sapiens <220> <221> MISC_FEATURE (222) (1) .. (31) <223> GLP-1 (7-37) <400> 2 His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly             20 25 30 <210> 3 <211> 30 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE (222) (1) .. (30) GLP-1 (7-36) amidated <220> <221> MISC_FEATURE &Lt; 222 > (30) <223> C-terminal amidation <400> 3 His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg             20 25 30 <210> 4 <211> 42 <212> PRT <213> Homo sapiens <220> <221> mat_peptide <222> (1) <223> gastric inhibitory polypeptide <400> 4 Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys 1 5 10 15 Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys             20 25 30 Lys Asn Asp Trp Lys His Asn Ile Thr Gln         35 40 <210> 5 <211> 29 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 61 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20. <400> 5 His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Ile His Gln Lys Glu Phe Ile Ala Trp Leu Met Asn Thr             20 25 <210> 6 <211> 29 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 62 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20. <400> 6 His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Ile His Gln Lys Glu Phe Ile Ala Trp Leu Met Asn Thr             20 25 <210> 7 <211> 29 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 63 <220> <221> MISC_FEATURE &Lt; 222 > (12) <223> Lactam bridge between residues 12 and 16. <400> 7 His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Ile His Gln Lys Glu Phe Ile Ala Trp Leu Met Asn Thr             20 25 <210> 8 <211> 29 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 66 <400> 8 His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Ile His Gln Lys Glu Phe Ile Ala Trp Leu Leu Ala Gln             20 25 <210> 9 <211> 29 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 68 <400> 9 His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Ile His Gln Glu Glu Phe Ile Ala Trp Leu Met Asn Thr             20 25 <210> 10 <211> 29 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 69 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 10 His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Ile His Gln Glu Glu Phe Ile Ala Trp Leu Met Asn Thr             20 25 <210> 11 <211> 29 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 84 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 11 His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Ile His Gln Lys Glu Phe Ile Cys Trp Leu Leu Ala Gln             20 25 <210> 12 <211> 29 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 85 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <220> <221> MISC_FEATURE &Lt; 222 > (24) <223> PEG (20 kDa) covalently attached to Cysteine <400> 12 His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Ile His Gln Lys Glu Phe Ile Cys Trp Leu Leu Ala Gln             20 25 <210> 13 <211> 29 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 92 <400> 13 His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Lys His Gln Lys Glu Phe Ile Ala Trp Leu Leu Ala Gln             20 25 <210> 14 <211> 29 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 93 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <220> <221> MISC_FEATURE <222> (17) <223> Lactam bridge between residues 17 and 21 <400> 14 His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Lys His Gln Lys Glu Phe Ile Ala Trp Leu Leu Ala Gln             20 25 <210> 15 <211> 29 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 95 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 15 His Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Glu 1 5 10 15 Ile His Gln Lys Asp Phe Val Asn Trp Leu Leu Ala Gln             20 25 <210> 16 <211> 29 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 96 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 16 Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Glu 1 5 10 15 Ile His Gln Lys Asp Phe Val Asn Trp Leu Leu Ala Gln             20 25 <210> 17 <211> 29 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 97 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 17 His Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Met Asp Glu 1 5 10 15 Ile His Gln Lys Asp Phe Val Asn Trp Leu Leu Ala Gln             20 25 <210> 18 <211> 29 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 98 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 18 Tyr Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Met Asp Glu 1 5 10 15 Ile His Gln Lys Asp Phe Val Asn Trp Leu Leu Ala Gln             20 25 <210> 19 <211> 42 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 99 <400> 19 Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys 1 5 10 15 Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys             20 25 30 Lys Asn Trp Leu Lys His Asn Ile Thr Gln         35 40 <210> 20 <211> 42 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 100 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <400> 20 Tyr Xaa Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys 1 5 10 15 Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys             20 25 30 Lys Asn Trp Leu Lys His Asn Ile Thr Gln         35 40 <210> 21 <211> 42 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 101 <400> 21 Tyr Ala Pro Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys 1 5 10 15 Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys             20 25 30 Lys Asn Trp Leu Lys His Asn Ile Thr Gln         35 40 <210> 22 <211> 42 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 102 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <400> 22 Tyr Xaa Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys 1 5 10 15 Ile His Gln Gln Asp Phe Val Cys Trp Leu Leu Ala Gln Lys Gly Lys             20 25 30 Lys Asn Trp Leu Lys His Asn Ile Thr Gln         35 40 <210> 23 <211> 42 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 104 <400> 23 Tyr Ala Pro Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys 1 5 10 15 Ile His Gln Gln Asp Phe Val Cys Trp Leu Leu Ala Gln Lys Gly Lys             20 25 30 Lys Asn Trp Leu Lys His Asn Ile Thr Gln         35 40 <210> 24 <211> 42 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 105 <220> <221> MISC_FEATURE &Lt; 222 > (24) <223> PEG (40 kDa) attached to Cysteine <400> 24 Tyr Ala Pro Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys 1 5 10 15 Ile His Gln Gln Asp Phe Val Cys Trp Leu Leu Ala Gln Lys Gly Lys             20 25 30 Lys Asn Trp Leu Lys His Asn Ile Thr Gln         35 40 <210> 25 <211> 29 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 106 <400> 25 Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys 1 5 10 15 Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln             20 25 <210> 26 <211> 29 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 107 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 26 His Ser Gln Gly Thr Phe Ile Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Ile His Gln Lys Glu Phe Ile Ala Trp Leu Met Asn Thr             20 25 <210> 27 <211> 29 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 108 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 27 His Ser Gln Gly Thr Phe Ile Ser Asp Tyr Ser Lys Ala Leu Asp Glu 1 5 10 15 Ile His Gln Lys Glu Phe Ile Ala Trp Leu Met Asn Thr             20 25 <210> 28 <211> 29 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 109 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 28 Tyr Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Ile His Gln Lys Asp Phe Val Asn Trp Leu Leu Ala Gln             20 25 <210> 29 <211> 29 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 110 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 29 Tyr Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Ile His Gln Lys Asp Phe Val Asn Trp Leu Leu Ala Gln             20 25 <210> 30 <211> 29 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 111 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 30 His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Ile His Gln Lys Asp Phe Val Asn Trp Leu Leu Ala Gln             20 25 <210> 31 <211> 24 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 113 <220> <221> MOD_RES <222> (1) <223> Xaa is 3-phenyllactic acid <220> <221> MISC_FEATURE &Lt; 222 > (11) <223> Lactam bridge between residues 11 and 15 <400> 31 Xaa Ile Ser Asp Tyr Ser Ile Ala Met Asp Glu Ile His Gln Lys Asp 1 5 10 15 Phe Val Asn Trp Leu Leu Ala Gln             20 <210> 32 <211> 24 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 114 <220> <221> MOD_RES <222> (1) <223> Xaa is 3-phenyllactic acid <220> <221> MISC_FEATURE &Lt; 222 > (11) <223> Lactam bridge between residues 11 and 15 <400> 32 Xaa Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu Ile His Gln Lys Asp 1 5 10 15 Phe Val Asn Trp Leu Leu Ala Gln             20 <210> 33 <211> 39 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 115 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 33 His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Ile His Gln Lys Asp Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 34 <211> 39 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 116 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 34 Tyr Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Ile His Gln Lys Asp Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 35 <211> 29 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 118 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 35 Tyr Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Ile His Gln Lys Glu Phe Val Asn Trp Leu Leu Ala Gln             20 25 <210> 36 <211> 39 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 120 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 36 Tyr Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 37 <211> 29 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 124 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 37 His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Met Asp Glu 1 5 10 15 Ile His Gln Lys Asp Phe Val Asn Trp Leu Leu Ala Gln             20 25 <210> 38 <211> 29 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 125 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 38 Tyr Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Met Asp Glu 1 5 10 15 Ile His Gln Lys Asp Phe Val Asn Trp Leu Leu Ala Gln             20 25 <210> 39 <211> 39 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 127 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 39 Tyr Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 40 <211> 39 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 128 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 40 His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Ile His Gln Lys Asp Phe Ile Ala Trp Leu Met Asn Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 41 <211> 39 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 129 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 41 Tyr Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Ile His Gln Lys Asp Phe Ile Ala Trp Leu Met Asn Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 42 <211> 39 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 139 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 42 Tyr Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 43 <211> 39 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 140 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 43 Tyr Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 44 <211> 39 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 141 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 44 Tyr Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Met Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 45 <211> 39 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 142 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 45 Tyr Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Met Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 46 <211> 39 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 143 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 46 Tyr Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 47 <211> 39 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 144 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 47 Tyr Ala Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Met Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 48 <211> 39 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 145 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 48 Tyr Ala Gln Gly Thr Phe Ile Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 49 <211> 39 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 146 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 49 Tyr Ala Gln Gly Thr Phe Ile Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 50 <211> 39 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 147 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 50 Tyr Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 51 <211> 39 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 148 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 51 Tyr Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 52 <211> 39 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 149 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 52 Tyr Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 53 <211> 39 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 150 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 53 Tyr Ser Gln Gly Thr Phe Ile Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 54 <211> 39 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 151 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 54 Tyr Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 55 <211> 39 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 152 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 55 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 56 <211> 39 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 154 <220> <221> MOD_RES <222> (1) <223> Xaa is hippuric acid <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 56 Xaa Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 57 <211> 39 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 155 <220> <221> MISC_FEATURE &Lt; 222 > (12) <223> Lactam bridge between residues 12 and 16 <400> 57 Tyr Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 58 <211> 39 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 156 <220> <221> MISC_FEATURE (222) (20) .. (24) <223> Lactam bridge between residues 20 and 24 <400> 58 Tyr Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Glu Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 59 <211> 39 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 157 <220> <221> MISC_FEATURE (222) (24) .. (28) <223> Lactam bridge between residues 24 and 28 <400> 59 Tyr Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Glu Trp Leu Leu Lys Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 60 <211> 39 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 158 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 60 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 61 <211> 39 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 162 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 61 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Tyr Tyr Leu Asp Glu 1 5 10 15 Gln Ala Val Lys Glu Phe Val Asn Trp Leu Ile Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 62 <211> 29 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 163 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 62 Tyr Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Ala Gly             20 25 <210> 63 <211> 29 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 164 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 63 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Ala Gly             20 25 <210> 64 <211> 40 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 165 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 64 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 65 <211> 40 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 166 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is d-field <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 65 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 66 <211> 39 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 167 <220> <221> MISC_FEATURE (222) (17) .. (20) <223> Lactam bridge between residues 17 and 20 <400> 66 Tyr Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Glu Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 67 <211> 39 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 168 <220> <221> MISC_FEATURE <222> (18) <223> Lactam bridge between residues 18 and 21 <400> 67 Tyr Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Lys Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 68 <211> 29 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 169 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 68 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Cys Trp Leu Leu Ala Gly             20 25 <210> 69 <211> 40 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 170 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> PEG (40 kDa) covalently attached to Cysteine <400> 69 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 70 <211> 29 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 172 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <220> <221> MISC_FEATURE &Lt; 222 > (24) <223> PEG (40 kDa) covalently attached to Cysteine <400> 70 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Cys Trp Leu Leu Ala Gly             20 25 <210> 71 <211> 40 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 174 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 71 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 72 <211> 39 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 175 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <220> <221> MISC_FEATURE &Lt; 222 > (24) <223> PEG (40 kDa) covalently attached to Cysteine <400> 72 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 73 <211> 40 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 176 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 73 Tyr Xaa Gln Gly Thr Phe Ile Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 74 <211> 29 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 177 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 74 Tyr Xaa Gln Gly Thr Phe Ile Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Cys Trp Leu Leu Ala Gly             20 25 <210> 75 <211> 40 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 178 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> PEG (40 kDa) covalently attached to Cysteine <400> 75 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 76 <211> 29 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 179 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <220> <221> MISC_FEATURE &Lt; 222 > (24) <223> PEG (40 kDa) covalently attached to Cysteine <400> 76 Tyr Xaa Gln Gly Thr Phe Ile Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Cys Trp Leu Leu Ala Gly             20 25 <210> 77 <211> 40 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 182 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> PEG (40 kDa) covalently attached to Cysteine <400> 77 Tyr Xaa Gln Gly Thr Phe Ile Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 78 <211> 29 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 186 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <220> <221> MISC_FEATURE &Lt; 222 > (24) <223> PEG (40 kDa) covalently attached to Cysteine <400> 78 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Cys Trp Leu Met Asn Gly             20 25 <210> 79 <211> 39 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 191 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <400> 79 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 80 <211> 34 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 192 <400> 80 Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu Gln Ala Ala Lys Glu 1 5 10 15 Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro             20 25 30 Pro Ser          <210> 81 <211> 38 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 194 <220> <221> MOD_RES <222> (1) <223> Xaa is Aib <400> 81 Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu Glu 1 5 10 15 Ala Val Arg Leu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser Ser             20 25 30 Gly Ala Pro Pro Ser         35 <210> 82 <211> 26 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 197 <220> <221> MISC_FEATURE (222) (13) .. (17) <223> Lactam bridge between residues 13 and 17 <400> 82 Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu Gln Ala Ala 1 5 10 15 Lys Glu Phe Val Asn Trp Leu Leu Ala Gly             20 25 <210> 83 <211> 28 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 198 <220> <221> MOD_RES <222> (1) <223> Xaa is Aib <220> <221> MISC_FEATURE (222) (15) .. (19) <223> Lactam bridge between residues 15 and 19 <400> 83 Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu Gln 1 5 10 15 Ala Ala Lys Glu Phe Val Asn Trp Leu Ala Gly             20 25 <210> 84 <211> 40 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 199 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 84 Tyr Xaa Gln Gly Thr Phe Val Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 85 <211> 40 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 200 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <220> <221> MOD_RES &Lt; 222 > (27) <223> Xaa is Nle <400> 85 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Xaa Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 86 <211> 39 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 201 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <400> 86 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Glu Ala Val Arg Leu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 87 <211> 40 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 202 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> PEG (40 kDa) covalently attached to Cysteine <400> 87 Tyr Xaa Gln Gly Thr Phe Val Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 88 <211> 40 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 203 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <220> <221> MOD_RES &Lt; 222 > (27) <223> Xaa is Nle <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> PEG (40 kDa) covalently attached to Cysteine <400> 88 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Xaa Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 89 <211> 40 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 204 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 89 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Arg Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 90 <211> 40 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 205 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> PEG (40 kDa) covalently attached to Cysteine <400> 90 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Arg Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 91 <211> 43 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 206 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 91 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Lys Gly Lys             20 25 30 Lys Asn Trp Leu Lys His Asn Ile Thr Gln Cys         35 40 <210> 92 <211> 43 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 207 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 92 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Lys Gly Lys             20 25 30 Lys Asn Trp Leu Lys His Asn Ile Thr Gln Cys         35 40 <210> 93 <211> 43 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 208 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <220> <221> MISC_FEATURE &Lt; 222 > (43) <223> PEG (40 kDa) covalently attached to Cysteine <400> 93 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Lys Gly Lys             20 25 30 Lys Asn Trp Leu Lys His Asn Ile Thr Gln Cys         35 40 <210> 94 <211> 40 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Analog 209 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE (222) (9) .. (12) <223> Lactam bridge between residues 9 and 12 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 94 Tyr Xaa Gln Gly Thr Phe Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 95 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> CEX <400> 95 Gly Pro Ser Ser Gly Ala Pro Pro Ser 1 5 10 <210> 96 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <222> (1) <223> Xaa is any amino acid <400> 96 Xaa Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser 1 5 10 <210> 97 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 97 Lys Arg Asn Arg Asn Asn Ile Ala 1 5 <210> 98 <211> 4 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <400> 98 Lys Arg Asn Arg One <210> 99 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-274 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> PEG (40 kDa) covalently attached to Cysteine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 99 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 100 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-311 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (24) <223> PEG (40 kDa) covalently attached to Cysteine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 100 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 101 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-298 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (24) <223> PEG (40 kDa) covalently attached to Cysteine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 16 Carbon fatty acyl group covalently attached to Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 101 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 102 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-309 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (24) <223> PEG (40 kDa) covalently attached to Cysteine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 14 Carbon fatty acyl group covalently attached Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 102 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 103 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-310 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (24) <223> PEG (40 kDa) covalently attached to Cysteine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 18 Carbon fatty acyl group covalently attached to Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 103 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 104 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-260 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 14 Carbon fatty acyl group covalently attached to Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 104 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 105 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-261 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 16 Carbon fatty acyl group covalently attached Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 105 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 106 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-262 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 18 Carbon fatty acyl group covalently attached to Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 106 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 107 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-252 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 107 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 108 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-255 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> PEG (40 kDa) attached to Cysteine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 108 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 109 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-256 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 109 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 110 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-257 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 110 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly             20 25 <210> 111 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-263 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 111 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 112 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-264 <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is Aib <400> 112 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Lea Ala Gly             20 25 <210> 113 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-265 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (24) <223> 14 Carbon fatty acyl group covalently attached to Lysine <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 113 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Lys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 114 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-266 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (24) <223> 16 Carbon fatty acyl group covalently attached to Lysine <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 114 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Lys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 115 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-267 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (24) <223> 18 Carbon fatty acyl group covalently attached to Lysine <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 115 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Lys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 116 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-268 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 116 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Lys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 117 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-269 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> 14 Carbon fatty acyl group covalently attached to Lysine <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 117 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 118 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-270 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> 16 Carbon fatty acyl group covalently attached to Lysine <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 118 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 119 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-271 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> 18 Carbon fatty acyl group covalently attached to Lysine <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 119 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 120 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-272 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 120 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 121 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-275 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (16) <223> Xaa is Orn <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 121 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 122 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-276 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (16) &Lt; 223 > Xaa is 2,4-diaminobutyric acid <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 122 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 123 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-277 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 14 Carbon fatty acyl group covalently attached to Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 123 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 124 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-278 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 16 Carbon fatty acyl group covalently attached to Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 124 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 125 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-279 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 18 Carbon fatty acyl group covalently attached to Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 125 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 126 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-280 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 126 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 127 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-281 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (24) <223> PEG (40 kDa) covalently attached to Cysteine <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 127 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly             20 25 <210> 128 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-282 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> 14 Carbon fatty acyl group covalently attached to Lysine <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 128 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Lea Ala Gly             20 25 <210> 129 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-283 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> 16 Carbon fatty acyl group covalently attached to Lysine <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 129 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Lea Ala Gly             20 25 <210> 130 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-284 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> 18 Carbon fatty acyl group covalently attached to Lysine <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 130 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Lea Ala Gly             20 25 <210> 131 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-285 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 131 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Lea Ala Gly             20 25 <210> 132 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-286 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 14 Carbon fatty acyl group covalently attached to Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 132 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 133 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-287 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 16 Carbon fatty acyl group covalently attached to Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 133 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 134 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-288 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 18 Carbon fatty acyl group covalently attached to Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 134 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 135 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-289 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 135 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 136 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-290 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (24) <223> PEG (40 kDa) covalently attached to Cysteine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 14 Carbon fatty acyl group covalently attached to Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 136 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 137 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-291 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (24) <223> PEG (40 kDa) covalently attached to Cysteine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 16 Carbon fatty acyl group covalently attached to Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 137 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 138 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-292 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (24) <223> PEG (40 kDa) covalently attached to Cysteine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 18 Carbon fatty acyl group covalently attached to Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 138 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 139 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-293 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (24) <223> PEG (40 kDa) covalently attached to Cysteine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 139 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 140 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-295 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> PEG (40 kDa) covalently attached to Cysteine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 140 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 141 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-296 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 16 Carbon fatty acyl group covalently attached to Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 141 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 142 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-297 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 16 Carbon fatty acyl group covalently attached to Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 142 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Met Asn Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 143 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-299 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (24) <223> PEG (40 kDa) covalently attached to Cysteine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 16 Carbon fatty acyl group covalently attached to Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 143 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Met Asn Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 144 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-306 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 14 Carbon fatty acyl group covalently attached to Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 144 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 145 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-307 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 18 Carbon fatty acyl group covalently attached to Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 145 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 146 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-308 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 146 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 147 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-322 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 3-SH-propionic acyl group covalently attached to Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 147 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 148 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-323 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 8 Carbon fatty acyl group covalently attached to Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 148 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 149 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-324 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 149 Tyr Xaa Gln Gly Thr Phe Ser Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 150 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-325 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES <222> (7) (7) &Lt; 223 > Xaa is 2-aminobutyric acid <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 150 Tyr Xaa Gln Gly Thr Phe Xaa Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 151 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-329 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 8 Carbon fatty acyl group covalently attached to Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 151 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 152 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-330 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 8 Carbon fatty acyl group covalently attached to Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 152 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 153 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-331 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (24) <223> PEG (40 kDa) covalently attached to Cysteine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 153 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 154 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-333 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (40) <223> Xaa is d-Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 14 Carbon fatty acyl group covalently attached to d-Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 154 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa         35 40 <210> 155 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-334 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (40) <223> Xaa is d-Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 155 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa         35 40 <210> 156 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-335 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (24) <223> PEG (40 kDa) covalently attached to Cysteine <220> <221> MOD_RES &Lt; 222 > (40) <223> Xaa is d-Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 14 Carbon fatty acyl group covalently attached to Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 156 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa         35 40 <210> 157 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-336 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (24) <223> PEG (40 kDa) covalently attached to Cysteine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> Xaa is d-Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 157 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa         35 40 <210> 158 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-337 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> 14 Carbon fatty acyl group covalently attached to Lysine <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 158 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 159 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-338 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 159 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 160 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-339 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 14 Carbon fatty acyl group covalently attached to Lysine <220> <221> MISC_FEATURE &Lt; 222 > (41) .. (41) <223> C-terminal amidation <400> 160 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ly Lys Cys         35 40 <210> 161 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-340 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (41) .. (41) <223> C-terminal amidation <400> 161 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ly Lys Cys         35 40 <210> 162 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-341 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> 14 Carbon fatty acyl group covalently attached to Lysine <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (24) <223> PEG (40 kDa) covalently attached to Cysteine <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 162 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 163 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-343 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 14 Carbon fatty acyl group covalently attached to Lysine <220> <221> MISC_FEATURE &Lt; 222 > (41) .. (41) <223> PEG (40 kDa) covalently attached to Cysteine <220> <221> MISC_FEATURE &Lt; 222 > (41) .. (41) <223> C-terminal amidation <400> 163 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ly Lys Cys         35 40 <210> 164 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-344 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (41) .. (41) <223> PEG (40 kDa) covalently attached to Cysteine <220> <221> MISC_FEATURE &Lt; 222 > (41) .. (41) <223> C-terminal amidation <400> 164 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ly Lys Cys         35 40 <210> 165 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-345 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 14 Carbon fatty acyl group covalently attached to Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 165 His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Met Asn Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 166 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-353 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (24) <223> PEG (40 kDa) covalently attached to Cysteine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 14 Carbon fatty acyl group covalently attached to Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 166 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 167 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-241 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (16) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 167 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 168 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-242 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (16) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 168 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Ala Gln Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 169 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-273 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (12) <223> Lactam bridge between residues 12 and 16 <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (40) <223> C-terminal amidation <400> 169 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 170 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <400> 170 Gly Pro Ser Ser Gly Ala Pro Pro Pro Lys 1 5 10 <210> 171 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MOD_RES <222> (1) <223> Xaa is Gly or a small, aliphatic or non-polar or slightly polar        amino acid <400> 171 Xaa Gly Pro Ser Ser Gly Ala Pro Pro Pro Lys 1 5 10 <210> 172 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MOD_RES <222> (1) <223> Xaa is Gly or a small, aliphatic or non-polar or slightly polar        amino acid <400> 172 Xaa Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser Lys 1 5 10 <210> 173 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synethic polypeptide <220> <221> MISC_FEATURE <223> mt-248 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (16) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> PEG (40 kDa) covalently attached to Cysteine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 173 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 174 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-249 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (16) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> PEG (40 kDa) covalently attached to Cysteine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 174 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Ala Gln Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 175 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-250 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (16) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 175 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 176 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-251 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 176 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 177 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-258 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 177 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly             20 25 <210> 178 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-259 <220> <221> MISC_FEATURE <223> C-terminal amidation <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <400> 178 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Ser 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly             20 25 <210> 179 <211> 30 <212> PRT <213> Artificial Sequene <220> <223> Synthetic polypeptide <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (24) <223> PEG (40 kDa) covalently attached to Cysteine <400> 179 His Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Val Lys Gly Arg             20 25 30 <210> 180 <211> 42 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 24 <220> <221> MISC_FEATURE &Lt; 222 > (24) Substituted amino acid covalently linked to hydrophilic group <400> 180 Tyr Ala Pro Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys 1 5 10 15 Ile His Gln Gln Asp Phe Val Xaa Trp Leu Leu Ala Gln Lys Gly Lys             20 25 30 Lys Asn Trp Leu Lys His Asn Ile Thr Gln         35 40 <210> 181 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 69 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <220> <221> MISC_FEATURE &Lt; 222 > (40) Substituted amino acid covalently linked to hydrophilic group <400> 181 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa         35 40 <210> 182 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 70 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <220> <221> MISC_FEATURE &Lt; 222 > (24) Substituted amino acid covalently linked to hydrophilic group <220> <221> misc_feature <222> (29). (29) <223> Xaa can be any naturally occurring amino acid <400> 182 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Xaa Trp Leu Leu Ala Xaa             20 25 <210> 183 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 72 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <220> <221> MISC_FEATURE &Lt; 222 > (24) Substituted amino acid covalently linked to hydrophilic group <400> 183 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Xaa Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 184 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 75 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <220> <221> MISC_FEATURE &Lt; 222 > (40) Substituted amino acid covalently linked to hydrophilic group <400> 184 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa         35 40 <210> 185 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Sythetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 76 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <220> <221> MISC_FEATURE &Lt; 222 > (24) Substituted amino acid covalently linked to hydrophilic group <400> 185 Tyr Xaa Gln Gly Thr Phe Ile Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Xaa Trp Leu Leu Ala Gly             20 25 <210> 186 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 77 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <220> <221> MISC_FEATURE &Lt; 222 > (40) Substituted amino acid covalently linked to hydrophilic group <400> 186 Tyr Xaa Gln Gly Thr Phe Ile Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa         35 40 <210> 187 <211> 29 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 78 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <220> <221> MISC_FEATURE &Lt; 222 > (24) Substituted amino acid covalently linked to hydrophilic group <400> 187 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Xaa Trp Leu Met Asn Gly             20 25 <210> 188 <211> 40 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 87 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> Substitute amino acid covalently linked to hydrophilic group <400> 188 Tyr Xaa Gln Gly Thr Phe Val Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa         35 40 <210> 189 <211> 40 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 88 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <220> <221> MOD_RES &Lt; 222 > (27) <223> Xaa is Nle <220> <221> MISC_FEATURE &Lt; 222 > (40) Substituted amino acid covalently linked to hydrophilic group <400> 189 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Xaa Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa         35 40 <210> 190 <211> 40 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 90 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <220> <221> MISC_FEATURE &Lt; 222 > (40) Substituted amino acid covalently linked to hydrophilic group <400> 190 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Arg Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa         35 40 <210> 191 <211> 43 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 93 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <220> <221> MISC_FEATURE &Lt; 222 > (43) Substituted amino acid covalently linked to hydrophilic group <400> 191 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Lys Gly Lys             20 25 30 Lys Asn Trp Leu Lys His Asn Ile Thr Gln Xaa         35 40 <210> 192 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 99 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) Substituted amino acid covalently linked to hydrophilic group <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 192 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa         35 40 <210> 193 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 100 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (24) Substituted amino acid covalently linked to hydrophilic group <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 193 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Xaa Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 194 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NOs: 101, 102, 103 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (24) Substituted amino acid covalently linked to hydrophilic group <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> Substitute amino acid covalently linked to an acyl or alkyl group <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 194 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Xaa Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa         35 40 <210> 195 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NOs: 104, 105, 106 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) Substituted amino acid covalently linked to an acyl or alkyl        group <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 195 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa         35 40 <210> 196 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 108 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) Substituted amino acid covalently linked to hydrophilic group <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 196 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa         35 40 <210> 197 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NOs: 113, 114, 115 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (24) Substituted amino acid covalently linked to acyl or alkyl group <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 197 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Xaa Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 198 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NOs: 117, 118, 119 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (10) Substituted amino acid covalently linked to acyl or alkyl group <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 198 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Xaa Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 199 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NOs: 123, 124, 125 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) Substituted amino acid covalently linked to acyl or alkyl group <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 199 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa         35 40 <210> 200 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 127 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (24) Substituted amino acid covalently linked to hydrophilic group <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 200 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Xaa Trp Leu Leu Ala Gly             20 25 <210> 201 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NOs: 128, 129, 130 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (10) Substituted amino acid covalently linked to acyl or alkyl group <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 201 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Xaa Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Lea Ala Gly             20 25 <210> 202 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 132 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) Substituted amino acid covalently linked acyl or alkyl group <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 202 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa         35 40 <210> 203 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NOs: 136, 137, 138 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (24) Substituted amino acid covalently linked to hydrophilic group <220> <221> MISC_FEATURE &Lt; 222 > (40) Substituted amino acid covalently linked to acyl or alkyl group <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 203 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Xaa Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa         35 40 <210> 204 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 139 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (24) Substituted amino acid covalently linked to hydrophilic group <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 204 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Xaa Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 205 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 140 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) Substituted amino acid covalently linked to hydrophilic group <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 205 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa         35 40 <210> 206 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 141 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) Substituted amino acid covalently linked to acyl or alkyl group <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 206 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa         35 40 <210> 207 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 142 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) Substituted amino acid covalently linked to acyl or alkyl group <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 207 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Met Asn Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa         35 40 <210> 208 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 143 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (24) Substituted amino acid covalently linked to hydrophilic group <220> <221> MISC_FEATURE &Lt; 222 > (40) Substituted amino acid covalently linked to acyl or alkyl group <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 208 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Xaa Trp Leu Met Asn Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa         35 40 <210> 209 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NOs: 144, 145 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) Substituted amino acid covalently linked to acyl or alkyl group <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 209 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa         35 40 <210> 210 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 148 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) Substituted amino acid covalently linked to acyl or alkyl group <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 210 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa         35 40 <210> 211 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 152 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) Substituted amino acid covalently linked to acyl or alkyl group <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 211 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa         35 40 <210> 212 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 152 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) Substituted amino acid covalently linked to acyl or alkyl group <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 212 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa         35 40 <210> 213 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 153 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (24) Substituted amino acid covalently linked to hydrophilic group <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 213 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Xaa Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 214 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 154 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) Substituted amino acid covalently linked to acyl or alkyl group <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 214 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa         35 40 <210> 215 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 156 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (24) Substituted amino acid covalently linked to hydrophilic group <220> <221> MISC_FEATURE &Lt; 222 > (40) Substituted amino acid covalently linked to acyl or alkyl group <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 215 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Xaa Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa         35 40 <210> 216 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 157 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (24) Substituted amino acid covalently linked to hydrophilic group <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 216 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Xaa Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa         35 40 <210> 217 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 235 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (10) Substituted amino acid covalently linked to acyl or alkyl group <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 217 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Xaa Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 218 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 160 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) Substituted amino acid covalently linked to acyl or alkyl group <220> <221> MISC_FEATURE &Lt; 222 > (41) .. (41) <223> C-terminal amidation <400> 218 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa Cys         35 40 <210> 219 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 162 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (10) Substituted amino acid covalently linked to acyl or alkyl group <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (24) Substituted amino acid covalently linked to hydrophilic group <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 219 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Xaa Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Xaa Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 220 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 163 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) Substituted amino acid covalently linked to acyl or alkyl group <220> <221> MISC_FEATURE &Lt; 222 > (41) .. (41) Substituted amino acid covalently linked to hydrophilic group <220> <221> MISC_FEATURE &Lt; 222 > (41) .. (41) <223> C-terminal amidation <400> 220 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa Xaa         35 40 <210> 221 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 164 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (41) .. (41) Substituted amino acid covalently linked to hydrophilic group <220> <221> MISC_FEATURE &Lt; 222 > (41) .. (41) <223> C-terminal amidation <400> 221 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Lys Xaa         35 40 <210> 222 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 165 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) Substituted amino acid covalently linked to acyl or alkyl group <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 222 His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Met Asn Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa         35 40 <210> 223 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 166 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (24) Substituted amino acid covalently linked to hydrophilic group <220> <221> MISC_FEATURE &Lt; 222 > (40) Substituted amino acid covalently linked to acyl or alkyl group <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 223 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Xaa Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa         35 40 <210> 224 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synethic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 173 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (16) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) Substituted amino acid covalently linked to hydrophilic group <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 224 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa         35 40 <210> 225 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE SEQ ID NO: 174 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (16) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) Substituted amino acid covalently linked to hydrophilic group <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 225 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Ala Gln Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Xaa         35 40 <210> 226 <211> 30 <212> PRT <213> Artificial Sequene <220> <223> Synthetic polypeptide <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (24) Substituted amino acid covalently linked to hydrophilic group <400> 226 His Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Cys Trp Leu Val Lys Gly Arg             20 25 30 <210> 227 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 227 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Lea Ala Gly             20 25 <210> 228 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MOD_RES <222> (2) (2) Xaa is D-Ser, DAla, Val, Gly, N-Methyl Ser, N-Methyl Ala, or Aib <220> <221> MOD_RES &Lt; 222 > (16) &Lt; 223 > Xaa is Lys, Glu, Ser, Orn, Dab, Aib or any alpha,        alpha-disubstituted amino acid <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is any alpha, alpha-disubstituted amino acid <220> <221> MOD_RES &Lt; 222 > (27) <223> Xaa is Ile, Leu, or Nle <220> <221> MOD_RES &Lt; 222 > (28) <223> Xaa is Ala or Gly <220> <221> MOD_RES <222> (29). (29) <223> Xaa is Thr, Ala, or Gly <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 228 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Xaa 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Xaa Xaa Xaa             20 25 <210> 229 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 229 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Arg Ala Xaa Asp Phe Val Gln Trp Leu Leu Ala Gly             20 25 <210> 230 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MOD_RES <222> (2) (2) Xaa is D-Ser, DAla, Val, Gly, N-Methyl Ser, N-Methyl Ala, or Aib <220> <221> MOD_RES &Lt; 222 > (16) &Lt; 223 > Xaa is Lys, Glu, Ser, Orn, Dab, Aib or any alpha,        alpha-disubstituted amino acid <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is any alpha, alpha-disubstituted amino acid <220> <221> MOD_RES &Lt; 222 > (27) <223> Xaa is Ile, Leu, or Nle <220> <221> MOD_RES &Lt; 222 > (28) <223> Xaa is Ala or Gly <220> <221> MOD_RES <222> (29). (29) <223> Xaa is Thr, Ala, or Gly <220> <221> MOD_RES <222> (29). (29) <223> C-terminal amidation <400> 230 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 1 5 10 15 Arg Arg Ala Xaa Asp Phe Val Gln Trp Leu Xaa Xaa Xaa             20 25 <210> 231 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Mt-354 <220> <221> MISC_FEATURE <223> Homodimer <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 14 Carbon fatty acyl group covalently bound to Lysine <220> <221> MOD_RES &Lt; 222 > (40) <223> C-terminal amidation <220> <221> DISULFID &Lt; 222 > (41) .. (41) &Lt; 223 > Disulfide bond formed with Cys residue of a second peptide having        the same structure. <400> 231 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ly Lys Cys         35 40 <210> 232 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Mt-356 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 232 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Met Asn Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 233 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Mt-357 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 233 Tyr Xaa Gln Gly Thr Phe Ile Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 234 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Mt-358 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 16 Carbon fatty acyl group covalently bound to Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 234 Tyr Xaa Gln Gly Thr Phe Ile Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 235 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Mt-367 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 16 Carbon fatty acyl group covalently bound to Lysine via a        gamma-Glu-gamma-Glu spacer <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 235 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 236 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Mt-368 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 16 Carbon fatty acyl group covalently bound to Lysine via a        gamma-Glu-gamma-Glu spacer <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 236 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 237 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Mt-369 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> 16 Carbon fatty acyl group covalently bound to Lysine via        gamma-Glu-gamma-Glu spacer <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 237 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 238 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Mt-376 <220> <221> MISC_FEATURE <223> Homodimer <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 14 Carbon fatty acyl group covelently bound to Lysine <220> <221> MISC_FEATURE &Lt; 222 > (41) .. (41) <223> C-terminal amidation <220> <221> MISC_FEATURE &Lt; 222 > (41) .. (41) <223> Cys residue covalently attached to 20 kDa PEG which is in turn        covalently attached to a Cys residue of a second peptide having        the same structure <400> 238 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ly Lys Cys         35 40 <210> 239 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Mt-377 <220> <221> MISC_FEATURE <223> homodimer <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 14 Carbon fatty acyl group covalently bound to Lysine <220> <221> MISC_FEATURE &Lt; 222 > (41) .. (41) <223> PEG (5 kDa) covalently bound to Cysteine <220> <221> MISC_FEATURE &Lt; 222 > (41) .. (41) <223> C-terminal amidation <220> <221> MISC_FEATURE &Lt; 222 > (41) .. (41) <223> Cys residue covalently attached to 5 kDa PEG which is in turn        covalently attached to a Cys residue of a second peptide having        the same structure <400> 239 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ly Lys Cys         35 40 <210> 240 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Peptide J <220> <221> MOD_RES &Lt; 222 > (3) <223> Xaa is a Glutamine analog <220> <221> MOD_RES &Lt; 222 > (27) <223> Xaa is Nle <400> 240 His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Thr 1 5 10 15 Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asp Glu             20 25 <210> 241 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> Peptide K <220> <221> MOD_RES &Lt; 222 > (3) <223> Xaa is a Glutamine analog <220> <221> MOD_RES &Lt; 222 > (16) <223> Xaa is Aib <400> 241 His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 1 5 10 15 Arg Arg Ala Ala Asp Phe Val Ala Trp Leu Met Asp Glu             20 25 <210> 242 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MOD_RES &Lt; 222 > (27) <223> Xaa is Nle <400> 242 His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Thr 1 5 10 15 Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asp Glu             20 25 <210> 243 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES &Lt; 222 > (3) <223> Xaa is Acetamidomethyl-cysteine <220> <221> MOD_RES &Lt; 222 > (27) <223> Xaa is Nle <400> 243 His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Thr 1 5 10 15 Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asp Glu             20 25 <210> 244 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES &Lt; 222 > (3) <223> Xaa is Acetyldiaminobutanoic acid <220> <221> MOD_RES &Lt; 222 > (27) <223> Xaa is Nle <400> 244 His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Thr 1 5 10 15 Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asp Glu             20 25 <210> 245 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MOD_RES &Lt; 222 > (3) <223> Xaa is carbamoyldiaminopropanoic acid <220> <221> MOD_RES &Lt; 222 > (27) <223> Xaa is Nle <400> 245 His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Thr 1 5 10 15 Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asp Glu             20 25 <210> 246 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MOD_RES &Lt; 222 > (3) &Lt; 223 > Xaa is Methylglutamine <220> <221> MOD_RES &Lt; 222 > (27) <223> Xaa is Nle <400> 246 His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Thr 1 5 10 15 Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asp Glu             20 25 <210> 247 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES &Lt; 222 > (3) <223> Xaa is Methionine sulfoxide <220> <221> MOD_RES &Lt; 222 > (27) <223> Xaa is Nle <400> 247 His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Thr 1 5 10 15 Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asp Glu             20 25 <210> 248 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES &Lt; 222 > (3) <223> Xaa is Acetylornithine <220> <221> MOD_RES &Lt; 222 > (27) <223> Xaa is Nle <400> 248 His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Thr 1 5 10 15 Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asp Glu             20 25 <210> 249 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MOD_RES &Lt; 222 > (16) <223> Xaa is Aib <400> 249 His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 1 5 10 15 Arg Arg Ala Ala Asp Phe Val Ala Trp Leu Met Asp Glu             20 25 <210> 250 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MOD_RES &Lt; 222 > (3) <223> Xaa is Acetyldiaminobutanoic acid <220> <221> MOD_RES &Lt; 222 > (16) <223> Xaa is Aib <400> 250 His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 1 5 10 15 Arg Arg Ala Ala Asp Phe Val Ala Trp Leu Met Asp Glu             20 25 <210> 251 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MOD_RES &Lt; 222 > (3) &Lt; 223 > Xaa is Methylglutamine <220> <221> MOD_RES &Lt; 222 > (16) <223> Xaa is Aib <400> 251 His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 1 5 10 15 Arg Arg Ala Ala Asp Phe Val Ala Trp Leu Met Asp Glu             20 25 <210> 252 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <400> 252 His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asp Thr             20 25 <210> 253 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MOD_RES &Lt; 222 > (3) <223> Xaa is Acetyldiaminobutanoic acid <220> <221> MOD_RES &Lt; 222 > (16) <223> Xaa is Aib <400> 253 His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 1 5 10 15 Arg Arg Ala Ala Asp Phe Val Ala Trp Leu Leu Asp Glu             20 25 <210> 254 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MOD_RES &Lt; 222 > (3) <223> Xaa is Acetyldiaminobutanoic acid <220> <221> MOD_RES &Lt; 222 > (16) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 254 His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 1 5 10 15 Arg Arg Ala Ala Asp Phe Val Ala Trp Leu Leu Asp Thr Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 255 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MOD_RES &Lt; 222 > (3) <223> Xaa is Acetyldiaminobutanoic acid <220> <221> MOD_RES &Lt; 222 > (16) <223> Xaa is Aib <400> 255 His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 1 5 10 15 Arg Arg Ala Ser Asp Phe Val Ser Trp Leu Leu Asp Glu             20 25 <210> 256 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MOD_RES &Lt; 222 > (3) <223> Xaa is Acetyldiaminobutanoic acid <220> <221> MOD_RES &Lt; 222 > (16) <223> Xaa is Aib <400> 256 His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 1 5 10 15 Arg Arg Ala Thr Asp Phe Val Thr Trp Leu Leu Asp Glu             20 25 <210> 257 <400> 257 000 <210> 258 <400> 258 000 <210> 259 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-225 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge links Glu16 and Lys20 <220> <221> MOD_RES &Lt; 222 > (40) <223> Epsilon amine of Lys is attached to Ala-Ac-Cys (PEG), where the        Ac-Cys (PEG) is a Cys residue containing an alpha amino group        capped with an acetyl group (CH3CO) and comprising a 40 kDa PEG        covalently attached to its side chain <400> 259 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 260 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-227 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge links Glu16 and Lys20 <220> <221> MOD_RES &Lt; 222 > (40) <223> Epsilon amine of Lys is attached to Arg-Ac-Cys (PEG), where the        Ac-Cys (PEG) is a Cys residue containing an alpha amino group        capped with an acetyl group (CH3CO) and comprising a 40 kDa PEG        covalently attached to its side chain <400> 260 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 261 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-294 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge links Glu16 and Lys20 <220> <221> MOD_RES &Lt; 222 > (40) <223> Cys-PEG covalently linked via thioether linkage <400> 261 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 262 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <400> 262 His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 263 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-217 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge <220> <221> MOD_RES &Lt; 222 > (24) <223> Epsilon amine is peptide bonded to Ala residue which is attached        to an acetylated Cys which is attached to a 40kDa PEG <220> <221> MOD_RES &Lt; 222 > (39) <223> C-terminal amidation <400> 263 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Lys Phe Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 264 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-218 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge <220> <221> MISC_FEATURE &Lt; 222 > (24) <223> Epsilon amine is peptide bonded to Glu residue which is attached        to an acetylated Cys which is attached to a 40kDa PEG <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 264 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Lys Phe Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 265 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-219 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge <220> <221> MOD_RES &Lt; 222 > (24) <223> Epsilon amine is peptide bonded to Arg residue which is attached        to an acetylated Cys which is attached to a 40kDa PEG <220> <221> MOD_RES &Lt; 222 > (39) <223> C-terminal amidation <400> 265 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Lys Phe Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 266 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-220 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge <220> <221> MOD_RES &Lt; 222 > (24) <223> Epsilon amine is peptide bonded to Phe residue which is attached        to an acetylated Cys which is attached to a 40kDa PEG <220> <221> MOD_RES &Lt; 222 > (39) <223> C-terminal amidation <400> 266 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Lys Phe Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 267 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-226 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge <220> <221> MOD_RES &Lt; 222 > (40) <223> Epsilon amine is peptide bonded to Glu residue which is attached        to an acetylated Cys which is attached to a 40kDa PEG <220> <221> MOD_RES &Lt; 222 > (40) <223> C-terminal amidation <400> 267 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 268 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-228 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> Epsilon amine is peptide bonded to Phe residue which is attached        to an acetylated Cys which is attached to a 40kDa PEG <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 268 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 269 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-402 <220> <221> MOD_RES <222> (2) (2) <223> Xaais AIB <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaais AIB <400> 269 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Lys Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 270 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-403 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is AIB <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MOD_RES &Lt; 222 > (40) <223> Acylated with C16 fatty acyl group via epsilon amine <400> 270 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Lys Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 271 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-404 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is AIB <400> 271 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Lys Ala Ala Glu Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 272 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-405 <220> <221> misc_feature <222> (2) (2) <223> Xaa can be any naturally occurring amino acid <220> <221> MOD_RES &Lt; 222 > (40) <223> Acylated with C16 fatty acyl group via epsilon amine <400> 272 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Lys Ala Ala Glu Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 273 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-395 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is AIB <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MOD_RES &Lt; 222 > (39) <223> C-terminal amidation <400> 273 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 274 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-396 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is AIB <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MOD_RES &Lt; 222 > (40) <223> C-terminal amidation <400> 274 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Glu         35 40 <210> 275 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-397 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is AIB <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MOD_RES &Lt; 222 > (40) <223> C-terminal amidation <400> 275 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ser Arg         35 40 <210> 276 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-398 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is AIB <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MOD_RES &Lt; 222 > (40) <223> D-Lys <220> <221> MOD_RES &Lt; 222 > (40) <223> C-terminal amidation <400> 276 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 277 <211> 29 <212> PRT <213> Homo sapiens <220> <221> MISC_FEATURE <223> Wild type glucagon <400> 277 His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr             20 25 <210> 278 <211> 42 <212> PRT <213> Homo sapiens <220> <221> mat_peptide <222> (1) <223> Gastric Inhibitory Polypeptide <400> 278 Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys 1 5 10 15 Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys             20 25 30 Lys Asn Asp Trp Lys His Asn Ile Thr Gln         35 40 <210> 279 <211> 30 <212> PRT <213> Artificial sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE (222) (1) .. (30) GLP-1 (7-36) amidated <220> <221> MISC_FEATURE &Lt; 222 > (30) <223> C-terminal amidation <400> 279 His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg             20 25 30 <210> 280 <211> 31 <212> PRT <213> Homo sapiens <220> <221> MISC_FEATURE (222) (1) .. (31) <223> GLP-1 (7-37) <400> 280 His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly             20 25 30 <210> 281 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 281 Gly Pro Ser Ser Gly Ala Pro Pro Ser 1 5 10 <210> 282 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 282 Gly Gly Pro Ser Ser Gly Ala Pro Pro Ser 1 5 10 <210> 283 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 283 Lys Arg Asn Arg Asn Asn Ile Ala 1 5 <210> 284 <211> 4 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 284 Lys Arg Asn Arg One <210> 285 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <400> 285 Gly Pro Ser Ser Gly Ala Pro Pro Pro Ly Lys 1 5 10 <210> 286 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-263 <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 286 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 287 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-402 <220> <221> misc_feature <222> (2) (2) <223> Xaa can be any naturally occurring amino acid <220> <221> misc_feature &Lt; 222 > (20) <223> Xaa can be any naturally occurring amino acid <400> 287 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Lys Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 288 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-403 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 288 His Ser Gln Gly Thr Phe Ile Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Ile His Gln Lys Glu Phe Ile Ala Trp Leu Met Asn Thr             20 25 <210> 289 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-404 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 289 His Ser Gln Gly Thr Phe Ile Ser Asp Tyr Ser Lys Ala Leu Asp Glu 1 5 10 15 Ile His Gln Lys Glu Phe Ile Ala Trp Leu Met Asn Thr             20 25 <210> 290 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-405 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 290 Tyr Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Ile His Gln Lys Asp Phe Val Asn Trp Leu Leu Ala Gln             20 25 <210> 291 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-395 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 291 His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Ile His Gln Lys Asp Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 292 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-396 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 292 Tyr Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Ile His Gln Lys Asp Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 293 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-397 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 293 Tyr Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Ile His Gln Lys Glu Phe Val Asn Trp Leu Leu Ala Gln             20 25 <210> 294 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-398 <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge between residues 16 and 20 <400> 294 Tyr Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 295 <211> 42 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-217 <400> 295 Tyr Ala Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys 1 5 10 15 Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys             20 25 30 Lys Asn Trp Leu Lys His Asn Ile Thr Gln         35 40 <210> 296 <211> 42 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-218 <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <400> 296 Tyr Xaa Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys 1 5 10 15 Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys             20 25 30 Lys Asn Trp Leu Lys His Asn Ile Thr Gln         35 40 <210> 297 <211> 42 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-219 <400> 297 Tyr Ala Pro Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys 1 5 10 15 Ile His Gln Gln Asp Phe Val Asn Trp Leu Leu Ala Gln Lys Gly Lys             20 25 30 Lys Asn Trp Leu Lys His Asn Ile Thr Gln         35 40 <210> 298 <211> 42 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-220 <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <400> 298 Tyr Xaa Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys 1 5 10 15 Ile His Gln Gln Asp Phe Val Cys Trp Leu Leu Ala Gln Lys Gly Lys             20 25 30 Lys Asn Trp Leu Lys His Asn Ile Thr Gln         35 40 <210> 299 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-225 <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge links Glu16 and Lys20 <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> Epsilon amine of Lys is attached to Ala-Ac-Cys (PEG), where the        Ac-Cys (PEG) is a Cys residue containing an alpha amino group        capped with an acetyl group (CH3CO) and comprising a 40 kDa PEG        covalently attached to its side chain <400> 299 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 300 <211> 42 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-226 <400> 300 Tyr Ala Pro Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys 1 5 10 15 Ile His Gln Gln Asp Phe Val Cys Trp Leu Leu Ala Gln Lys Gly Lys             20 25 30 Lys Asn Trp Leu Lys His Asn Ile Thr Gln         35 40 <210> 301 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-227 <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Lactam bridge links Glu16 and Lys20 <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> Epsilon amine of Lys is attached to Arg-Ac-Cys (PEG), where the        Ac-Cys (PEG) is a Cys residue containing an alpha amino group        capped with an acetyl group (CH3CO) and comprising a 40 kDa PEG        covalently attached to its side chain <400> 301 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 302 <211> 42 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-228 <220> <221> MISC_FEATURE &Lt; 222 > (24) <223> PEG (40kDa) bound to Cysteine <400> 302 Tyr Ala Pro Gly Thr Phe Ile Ser Asp Tyr Ser Ile Ala Met Asp Lys 1 5 10 15 Ile His Gln Gln Asp Phe Val Cys Trp Leu Leu Ala Gln Lys Gly Lys             20 25 30 Lys Asn Trp Leu Lys His Asn Ile Thr Gln         35 40 <210> 303 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Sythetic peptide <220> <221> MISC_FEATURE <223> Analog # 29 <220> <221> MISC_FEATURE <222> (2) (2) <223> d-Ser <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via gamma-Glu spacer <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 303 His Ser Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 304 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> Analog # 30 <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via gamma-Glu spacer <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 304 His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 305 <211> 31 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> Analog # 34 <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via gamma-Glu spacer <220> <221> MISC_FEATURE &Lt; 222 > (31) <223> C-terminal amidation <400> 305 His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Arg Gly             20 25 30 <210> 306 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> Analog # 36 <220> <221> MISC_FEATURE <222> (2) (2) <223> d-Ser <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via gamma-Glu spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 306 His Ser Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Xaa Glu Phe Val Gln Trp Leu Leu Asp Thr             20 25 <210> 307 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> Analog # 37 <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via gamma-Glu spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 307 His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Xaa Glu Phe Val Gln Trp Leu Leu Asp Thr             20 25 <210> 308 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Sythetic peptide <220> <221> MISC_FEATURE <223> Analog # 44 <220> <221> MISC_FEATURE <222> (1) &Lt; 223 > Xaa is DMIA <220> <221> MISC_FEATURE <222> (2) (2) <223> d-Ser <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with C16 fatty acyl group via gamma-Glu spacer <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 308 Xaa Ser Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Thr             20 25 <210> 309 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> Analog # 49 <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via gamma-Glu-gamma-Glu        spacer <220> <221> MISC_FEATURE &Lt; 222 > (16) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 309 His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Met Asp Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 310 <400> 310 000 <210> 311 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> Analog # 53 <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via gamma-Glu-gamma-Glu        spacer <220> <221> MISC_FEATURE &Lt; 222 > (16) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 311 His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Val Lys Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 312 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> Analog # 54 <220> <221> misc_feature <222> (2) (2) <223> Xaa can be any naturally occurring amino acid <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with C16 fatty acyl group via gamma-Glu-gamma-Glu spacer <220> <221> MISC_FEATURE &Lt; 222 > (16) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (16) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 312 His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Lys Asp Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 313 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Sythetic peptide <220> <221> MISC_FEATURE <223> Analog # 61 <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via gamma-Glu spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 313 His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Xaa Glu Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 314 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> Analog # 62 <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via gamma-Glu spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 314 His Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Xaa Glu Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 315 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> Analog # 63 <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via gamma-Glu spacer <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 315 His Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 316 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> Analog # 64 <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via gamma-Glu spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 316 His Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Xaa Glu Phe Val Gln Trp Leu Leu Asp Thr             20 25 <210> 317 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> Analog # 65 <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via gamma-Glu spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 317 His Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Xaa Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 318 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (16) <223> Xaa is AIB <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 318 His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr             20 25 <210> 319 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (9) <223> Acylated with a C16 fatty acyl group via gamma-Glu-gamma-Glu        spacer <220> <221> MISC_FEATURE &Lt; 222 > (16) <223> Xaa is AIB <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 319 His Xaa Gln Gly Thr Phe Thr Ser Lys Tyr Ser Lys Tyr Leu Asp Xaa 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr             20 25 <210> 320 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via gamma-Glu-gamma-Glu        spacer <220> <221> MISC_FEATURE &Lt; 222 > (16) <223> Xaa is AIB <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 320 His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr             20 25 <210> 321 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE (12). (12) <223> Acylated with a C16 fatty acyl group via gamma-Glu-gamma-Glu        spacer <220> <221> MISC_FEATURE &Lt; 222 > (16) <223> Xaa is AIB <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 321 His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr             20 25 <210> 322 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Sythetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (16) <223> Acylated with a C16 fatty acyl group via gamma-Glu-gamma-Glu        spacer <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 322 His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr             20 25 <210> 323 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (16) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Acylated with a C16 fatty acyl group via gamma-Glu-gamma-Glu        spacer <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 323 His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr             20 25 <210> 324 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> d-Ser <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 324 His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 325 <400> 325 000 <210> 326 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> d-Ser <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 326 Tyr Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 327 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> d-Ser <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> Covalently bound to 40 kDa PEG via thioether made by reaction of        peptide with haloacetyl-activated PEG <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 327 Tyr Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 328 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 328 His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 329 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> Covalently bound to 40 kDa PEG via thioether made by reaction of        peptide with haloacetyl-activated PEG <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 329 His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 330 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (24) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 330 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Xaa Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 331 <400> 331 000 <210> 332 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE <222> (16) .. (20) <223> Linked via lactam bridge <220> <221> MISC_FEATURE &Lt; 222 > (24) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 332 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Val Xaa Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 333 <400> 333 000 <210> 334 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE <222> (17) <223> Linked via lactam bridge <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 334 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Glu Ala Ala Xaa Lys Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 335 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE <222> (17) <223> Linked via lactam bridge <220> <221> MISC_FEATURE &Lt; 222 > (21) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> Covalently bound to 40 kDa PEG via thioether made by reaction of        peptide with haloacetyl-activated PEG <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 335 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Glu Ala Ala Xaa Lys Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 336 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is 1-aminocyclopropane-1-carboxylate <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 336 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 337 <400> 337 000 <210> 338 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C14 acyl group via gamma-Glu spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 338 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 339 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C14 fatty acyl group via gamma-Glu spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> Covalently bound to 40 kDa PEG via thioether made by reaction of        peptide with haloacetyl-activated PEG <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 339 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 340 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> Acylated with a C14 fatty acyl group via gamma-Glu spacer <220> <221> MISC_FEATURE &Lt; 222 > (41) .. (41) <223> C-terminal amidation <400> 340 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ly Lys Gly         35 40 <210> 341 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> Acylated with a C14 fatty acyl group via gamma-Glu spacer <220> <221> MISC_FEATURE &Lt; 222 > (41) .. (41) <223> Covalently bound to a 40 kDa PEG via thioether made by reaction of        peptide with maleimide-activated PEG <220> <221> MISC_FEATURE &Lt; 222 > (41) .. (41) <223> C-terminal amidation <400> 341 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ly Lys Cys         35 40 <210> 342 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> Covalently bound to 40 kDa PEG via thioether made by reactioni of        peptide with a maleimide-activated PEG <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 342 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 343 <400> 343 000 <210> 344 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C14 fatty acyl group via gamma-Glu spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> Covalently bound to 40 kDa PEG via thioether made by reaction of        peptide with maleimide-actived PEG <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 344 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 345 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via gamma-Glu spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> Covalently bound to 40 kDa PEG via thioether made by reaction of        peptide with maleimide-activated PEG <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 345 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 346 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (24) <223> Covalently bound to 40 kDa PEG via thioether made by reaction of        peptide with maleimide-actived PEG <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> Acylated with a C16 fatty acyl group <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 346 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 347 <400> 347 000 <210> 348 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> Covalently bound to 40 kDa PEG via thioether made by reaction of        peptide with haloacetyl-actived PEG <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 348 Tyr Xaa Glu Gly Thr Phe Ile Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 349 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptid <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is 1-aminocyclopropane-1-carboxylate <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> Covalently bound to 40 kDa PEG via thioether made by reaction of        peptide with a haloacetyl-activaed PEG <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 349 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 350 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is 1-aminocyclopropane-1-carboxylate <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> Covalently bound to 40 kDa PEG via thioether made by reaction of        peptide and haloacetyl-activated PEG <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 350 His Xaa Gln Gly Thr Phe Ile Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 351 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is 1-aminocyclopropane-1-carboxylate <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> Covalently bound to 40 kDa PEG via thioether made by reaction of        peptide with haloacetyl-activated PEG <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 351 Tyr Xaa Gln Gly Thr Phe Ile Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 352 <211> 31 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via gamma-Glu spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (31) <223> C-terminal amidation <400> 352 His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Xaa Glu Phe Val Gln Trp Leu Leu Asp Gly Arg Gly             20 25 30 <210> 353 <211> 31 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> d-Ser <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via gamma-Glu spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (31) <223> C-terminal amiation <400> 353 His Ser Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Xaa Glu Phe Val Gln Trp Leu Leu Asp Gly Arg Gly             20 25 30 <210> 354 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> d-Ser <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via gamma-Glu spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 354 His Ser Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Xaa Glu Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 355 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptid <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via gamma-Glu spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 355 His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Xaa Glu Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 356 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with C16 fatty acyl group via gamma-Glu spacer <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 356 His Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 357 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with C16 fatty acyl group via gamma-Glu-gamma-Glu spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 357 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 358 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with C16 fatty acyl group via gamma-Glu-gamma-Glu spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 358 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 359 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via gamma-Glu spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 359 His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Xaa Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 360 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with C16 fatty acyl group via gamma-Glu spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 360 His Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Xaa Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 361 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptid <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via gamma-Glu spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 361 His Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Xaa Glu Phe Val Gln Trp Leu Leu Asp Thr             20 25 <210> 362 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> Acylated with a C16 fatty acyl group <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 362 His Xaa Glu Gly Thr Phe Ile Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Met Asn Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 363 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> Acylated with C16 fatty acyl group <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 363 His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 364 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> Acylated with a C16 fatty acyl group <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 364 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 365 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> Acylated with a C16 fatty acyl group via gamma-Glu-gamma-Glu        spacer <220> <221> MISC_FEATURE &Lt; 222 > (41) .. (41) <223> C-terminal amidation <400> 365 His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ly Lys Gly         35 40 <210> 366 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via gamma-Glu-gamma-Glu        spacer <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 366 His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 367 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via gamma-Glu-gamma-Glu        spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 367 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Asp Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 368 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via gamma-Glu-gamma-Glu        spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 368 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Asp Thr             20 25 <210> 369 <400> 369 000 <210> 370 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Sythetic peptide <220> <221> MISC_FEATURE <223> Analog # 29 <220> <221> MISC_FEATURE <222> (2) (2) <223> d-Ser <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via acid amino acid spacer <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 370 His Ser Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 371 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> Analog # 30 <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via acid amino acid spacer <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 371 His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 372 <211> 31 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> Analog # 34 <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via acidic amino acid spacer <220> <221> MISC_FEATURE &Lt; 222 > (31) <223> C-terminal amidation <400> 372 His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Arg Gly             20 25 30 <210> 373 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> Analog # 36 <220> <221> MISC_FEATURE <222> (2) (2) <223> d-Ser <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via acidic amino acid spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 373 His Ser Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Xaa Glu Phe Val Gln Trp Leu Leu Asp Thr             20 25 <210> 374 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> Analog # 37 <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via acidic amino acid spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 374 His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Xaa Glu Phe Val Gln Trp Leu Leu Asp Thr             20 25 <210> 375 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Sythetic peptide <220> <221> MISC_FEATURE <223> Analog # 44 <220> <221> MISC_FEATURE <222> (1) &Lt; 223 > Xaa is DMIA <220> <221> MISC_FEATURE <222> (2) (2) <223> d-Ser <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with C16 fatty acyl group via acidic amino acid spacer <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 375 Xaa Ser Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Thr             20 25 <210> 376 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> Analog # 49 <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via dipeptide spacer <220> <221> MISC_FEATURE &Lt; 222 > (16) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 376 His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Met Asp Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 377 <400> 377 000 <210> 378 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> Analog # 53 <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via dipeptide spacer <220> <221> MISC_FEATURE &Lt; 222 > (16) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 378 His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Val Lys Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 379 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> Analog # 54 <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with C16 fatty acyl group via acidic amino acid spacer <220> <221> MISC_FEATURE &Lt; 222 > (16) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 379 His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Lys Asp Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 380 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Sythetic peptide <220> <221> MISC_FEATURE <223> Analog # 61 <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via acidic amino acid spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 380 His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Xaa Glu Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 381 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> Analog # 62 <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via acidic amino acid spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 381 His Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Xaa Glu Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 382 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> Analog # 63 <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via acidic amino acid spacer <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 382 His Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 383 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> Analog # 64 <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via acidic amino acid spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 383 His Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Xaa Glu Phe Val Gln Trp Leu Leu Asp Thr             20 25 <210> 384 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> Analog # 65 <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via acidic amino acid spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 384 His Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Xaa Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 385 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (9) <223> Acylated with a C16 fatty acyl group via dipeptide spacer <220> <221> MISC_FEATURE &Lt; 222 > (16) <223> Xaa is AIB <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 385 His Xaa Gln Gly Thr Phe Thr Ser Lys Tyr Ser Lys Tyr Leu Asp Xaa 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr             20 25 <210> 386 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via dipeptide spacer <220> <221> MISC_FEATURE &Lt; 222 > (16) <223> Xaa is AIB <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 386 His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr             20 25 <210> 387 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE (12). (12) <223> Acylated with a C16 fatty acyl group via dipeptide spacer <220> <221> MISC_FEATURE &Lt; 222 > (16) <223> Xaa is AIB <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 387 His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr             20 25 <210> 388 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Sythetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (16) <223> Acylated with a C16 fatty acyl group via dipeptide spacer <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 388 His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15 Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr             20 25 <210> 389 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (16) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Acylated with a C16 fatty acyl group via dipeptide spacer <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 389 His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 1 5 10 15 Arg Arg Ala Lys Asp Phe Val Gln Trp Leu Met Asn Thr             20 25 <210> 390 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C14 acyl group via acidic amino acid spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 390 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 391 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C14 fatty acyl group via acidic amino acid spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> Covalently bound to 40 kDa PEG via thioether made by reaction of        peptide with haloacetyl-activated PEG <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 391 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 392 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> Acylated with a C14 fatty acyl group via acidic amino acid spacer <220> <221> MISC_FEATURE &Lt; 222 > (41) .. (41) <223> C-terminal amidation <400> 392 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ly Lys Gly         35 40 <210> 393 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> Acylated with a C14 fatty acyl group via acidic amino acid spacer <220> <221> MISC_FEATURE &Lt; 222 > (41) .. (41) <223> Covalently bound to a 40 kDa PEG via thioether made by reaction of        peptide with maleimide-activated PEG <220> <221> MISC_FEATURE &Lt; 222 > (41) .. (41) <223> C-terminal amidation <400> 393 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ly Lys Cys         35 40 <210> 394 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C14 fatty acyl group via acidic amino acid spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> Covalently bound to 40 kDa PEG via thioether made by reaction of        peptide with maleimide-actived PEG <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 394 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 395 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via acidic amino acid spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> Covalently bound to 40 kDa PEG via thioether made by reaction of        peptide with maleimide-activated PEG <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 395 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Cys         35 40 <210> 396 <211> 31 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via acidic amino acid spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (31) <223> C-terminal amidation <400> 396 His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Xaa Glu Phe Val Gln Trp Leu Leu Asp Gly Arg Gly             20 25 30 <210> 397 <211> 31 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> d-Ser <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via acidic amino acid spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (31) <223> C-terminal amiation <400> 397 His Ser Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Xaa Glu Phe Val Gln Trp Leu Leu Asp Gly Arg Gly             20 25 30 <210> 398 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> d-Ser <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via acidic amino acid spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 398 His Ser Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Xaa Glu Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 399 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via acidic amino acid spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 399 His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Xaa Glu Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 400 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with C16 fatty acyl group via acidic amino acid spacer <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 400 His Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 401 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with C16 fatty acyl group via dipeptide spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 401 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 402 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with C16 fatty acyl group via dipeptide spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 402 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 403 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via acidic amino acid spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 403 His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Xaa Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 404 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with C16 fatty acyl group via acidic amino acid spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 404 His Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Xaa Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 405 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptid <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via acidic amino acid spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 405 His Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Arg Ala Xaa Glu Phe Val Gln Trp Leu Leu Asp Thr             20 25 <210> 406 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> Acylated with a C16 fatty acyl group via dipeptide spacer <220> <221> MISC_FEATURE &Lt; 222 > (41) .. (41) <223> C-terminal amidation <400> 406 His Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Pro Ly Lys Gly         35 40 <210> 407 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via dipeptide spacer <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 407 His Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 Arg Ala Ala Gln Asp Phe Val Gln Trp Leu Leu Asp Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 408 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via dipeptide spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 408 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Asp Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 409 <211> 29 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via dipeptide spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> C-terminal amidation <220> <221> MISC_FEATURE <222> (29). (29) <223> C-terminal amidation <400> 409 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Asp Thr             20 25 <210> 410 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-261 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 16 Carbon fatty acyl group covalently attached Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 410 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 411 <211> 40 <212> PRT <213> Artificial Sequence <220> <223> Synthetic polypeptide <220> <221> MISC_FEATURE <223> mt-278 <220> <221> MOD_RES <222> (2) (2) <223> Xaa is Aib <220> <221> MOD_RES &Lt; 222 > (20) <223> Xaa is Aib <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> 16 Carbon fatty acyl group covalently attached to Lysine <220> <221> MISC_FEATURE &Lt; 222 > (40) <223> C-terminal amidation <400> 411 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Tyr Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser Ser         35 40 <210> 412 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-384 <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via gamma-Glu-gamma-Glu        spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation &Lt; 400 > 412 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35 <210> 413 <211> 39 <212> PRT <213> Artificial Sequence <220> <223> Synthetic peptide <220> <221> MISC_FEATURE <223> mt-384 <220> <221> MISC_FEATURE <222> (2) (2) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (10) <223> Acylated with a C16 fatty acyl group via dipeptide spacer <220> <221> MISC_FEATURE &Lt; 222 > (20) <223> Xaa is AIB <220> <221> MISC_FEATURE &Lt; 222 > (39) <223> C-terminal amidation <400> 413 Tyr Xaa Gln Gly Thr Phe Thr Ser Asp Lys Ser Ile Tyr Leu Asp Lys 1 5 10 15 Gln Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser             20 25 30 Ser Gly Ala Pro Pro Ser         35

Claims (24)

A method of reducing weight gain or causing weight loss, wherein the extended half-life glucagon-like peptide-1 (GLP-1) / glucose dependent insulinotropic in adult humans requiring reduced weight gain or induced weight loss peptide) A method comprising administering a coagonist peptide in a weekly dosage of about 1 mg to about 40 mg. The method of claim 1, wherein the weekly dose is about 2 mg to about 10 mg. The method of claim 1, wherein the adult human has overweight, type II diabetes, insulin resistance, alcoholic liver disease, non-alcoholicic fatty liver disease (NAFLD), or metabolic syndrome. . A method for treating hyperglycemia, reducing blood sugar levels, or normalizing blood glucose levels, wherein the extended half-life GLP-1 / GIP coagent peptides in adult humans in need of treatment of hyperglycemia, reduction of blood sugar levels, or normalization of blood sugar levels Administering a weekly dose of about 1 mg to about 40 mg per week. The method of claim 4, wherein the weekly dose is about 2 mg to about 10 mg. 6. The method of claim 4 or 5, wherein the adult human has type I diabetes, type II diabetes or gestational diabetes. The method of claim 1, wherein the extended half-life GLP-1 / GIP coagent peptide is administered once per week. 7. The method of claim 1, wherein the extended half-life GLP-1 / GIP coagent peptide is administered twice per week. The method of claim 1, wherein the extended half-life GLP-1 / GIP coagent peptide expresses GLP-1 percent titer within about 10 times the GIP percent potency. Way. The method according to any one of the preceding claims, wherein the extended half-life of GLP-1 / GIP co-agent peptides to having the EC ₅₀ of the GLP-1 receptor in a less than 10 times the EC ₅₀ at the GIP receptor Way. 11. The method of claim 1, wherein the extended half-life GLP-1 / GIP coagent peptide expresses at least 1% GIP percent titer or at least 1% GLP-1 percent titer. . The method of claim 1, wherein the extended half-life GLP-1 / GIP coagent peptide expresses a half-life of about 4 days to about 7 days. The method of claim 1, wherein the extended half-life GLP-1 / GIP coagent peptide comprises a polyethylene glycol moiety having a molecular weight of about 30,000 Daltons to about 60,000 Daltons. . The method of claim 13, wherein the polyethylene glycol moiety has a molecular weight of about 40,000 Daltons. The method of claim 1, wherein the extended half-life GLP-1 / GIP coagent peptide is any one of SEQ ID NOs: 5 to 94, 99 to 169, 173 to 413, or SEQ ID NOs: 5 to 94 , Amino acid sequence comprising up to six amino acid modifications as compared to any one of 99 to 169, 173 to 413. The method of claim 15, wherein the GLP-1 / GIP coagent peptide is any one of SEQ ID NOs: 75, 99 to 103, 140, 153, 166 and 261, or SEQ ID NOs: 75, 99 to 103, 140, 153, 166 and And an amino acid sequence comprising up to six amino acid modifications as compared to any one of 261. 17. The method of any one of claims 1-16, further comprising administering a second therapeutic agent. The method of claim 17, wherein the second therapeutic agent is an antidiabetic agent. The method of claim 18, wherein the second therapeutic agent is an anti-obesity agent. 20. The method of any one of claims 1-19, wherein said extended half-life GLP-1 / GIP coagent peptide is administered in a pharmaceutical composition. The method of claim 20, wherein the pharmaceutical composition is administered via subcutaneous, intravenous or intramuscular injection. The method of claim 21, wherein the pharmaceutical composition is administered by subcutaneous injection. 5. The method of claim 1 or 4, wherein the administration of the extended half-life GLP-1 / GIP coagent peptide is to increase insulin levels, decrease glucose levels, increase C-peptide levels, decrease HbA _1c levels or fructose. Causing a decrease in the level of civil, or any combination thereof. 24. The method of any one of claims 20-23, wherein the extended half-life GLP-1 / GIP coagent peptide is administered from a prefilled syringe.

Images